U.S. patent number 8,679,103 [Application Number 12/642,021] was granted by the patent office on 2014-03-25 for two step mammalian biofilm treatment processes and systems.
This patent grant is currently assigned to Valam Corporation. The grantee listed for this patent is Yosef Krespi. Invention is credited to Yosef Krespi.
United States Patent |
8,679,103 |
Krespi |
March 25, 2014 |
Two step mammalian biofilm treatment processes and systems
Abstract
A two-step mammalian biofilm treatment process can have a first
step of disrupting or dispersing an undesired biofilm present at a
treatment site in or on a mammalian host by suitable mechanical
action for example, by applying irrigation fluid, sonic or other
vibration, a mechanical instrument or laser-generated mechanical
shockwaves to the biofilm. The treatment can also have a second
step comprising applying an antimicrobial treatment to the
mammalian host to control possible infection related to biofilm
dispersed in the first step or to residual biofilm at the treatment
site. Usefully, the second step can be performed within a limited
time period after the first step. The process can also include
additional steps The antimicrobial treatment can employ light or an
antibiotic material. Included are implants cleaned of biofilm by a
described process.
Inventors: |
Krespi; Yosef (New York,
NY) |
Applicant: |
Name |
City |
State |
Country |
Type |
Krespi; Yosef |
New York |
NY |
US |
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Assignee: |
Valam Corporation (New York,
NY)
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Family
ID: |
42267152 |
Appl.
No.: |
12/642,021 |
Filed: |
December 18, 2009 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20100160838 A1 |
Jun 24, 2010 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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61139850 |
Dec 22, 2008 |
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Current U.S.
Class: |
606/16; 606/2;
606/13; 128/898 |
Current CPC
Class: |
A61N
5/0624 (20130101); A61B 18/26 (20130101); A61N
5/0601 (20130101); A61N 2005/063 (20130101); A61M
31/00 (20130101); A61N 2005/0661 (20130101); A61N
7/00 (20130101); A61N 2005/0659 (20130101); A61N
2005/0607 (20130101); A61N 2005/067 (20130101) |
Current International
Class: |
A61B
18/18 (20060101) |
Field of
Search: |
;606/16,13,2
;128/898 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO0067917 |
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Nov 2000 |
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WO |
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WO200867361 |
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Dec 2008 |
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WO |
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Other References
Soukos et al., "Photomechanical Drug Delivery into Bacterial
Biofilms", Pharmaceutical Research, vol. 17, No. 4, 2000, pp.
405-409. cited by applicant .
Soukos et al., "Photomechanical wave-assisted molecular delivery in
oral biofilms", World J Microbial Biotechnol (2007) 23, pp.
1637-1646. cited by applicant .
Krespi et al., "Laser Disruption of Biofilm", Laryngoscope 118,
Jul. 2008, pp. 1168-1173. cited by applicant.
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Primary Examiner: Park; Kinam
Attorney, Agent or Firm: K&L Gates LLP
Parent Case Text
CROSS REFERENCE TO A RELATED APPLICATION
This application claims the benefit of provisional patent
application No. 61/139,850, filed on Dec. 22, 2008, the entire
disclosure of which is incorporated by reference herein.
Claims
The invention claimed is:
1. A two-step mammalian biofilm treatment process comprising: a
first step of dispersing an undesired biofilm present at a
treatment site in or on a mammalian host by mechanically disrupting
the biofilm, the disrupting comprising applying laser-generated
mechanical shockwaves to the biofilm; and a second step comprising
applying an antimicrobial treatment to the mammalian host, the
antimicrobial treatment comprising applying an antimicrobial dosage
of light to the treatment site, to control possible infection
related to the biofilm dispersed in the first step or to residual
biofilm at the treatment site; wherein the second step is performed
within a limited time period after the first step.
2. The process according to claim 1 wherein the limited time period
is selected from the group consisting of 48 hours, 24 hours, 3
hours, 1 hour, 30 minutes and 10 minutes after the application of
laser-generated mechanical shockwaves.
3. The process according to claim 1 wherein the second step
comprises diffusing the-antimicrobial dosage of light onto the
treatment site and in the vicinity of the treatment site.
4. The process according to claim 3, further comprising applying
the-antimicrobial dosage of light to at least one other site on or
in the mammalian host subject to material dispersed from the
biofilm in the first step.
5. The process according to claim 1 wherein the antimicrobial
dosage of light reduces or controls at least one species of the
microorganisms in the biofilm.
6. The process according to claim 1 wherein the biofilm comprises
matter foreign to the mammalian host and the first step further
comprises mechanically disrupting the biofilm.
7. The process according to claim 1 wherein the biofilm is attached
to the treatment site and the first step comprises one or more
steps selected from the group steps consisting of: directing the
mechanical shockwaves toward the biofilm at the treatment site;
oscillating the biofilm by the application of the mechanical
shockwaves; and tearing one or more pieces of the biofilm away from
residual biofilm at the treatment site or from the treatment site
by applying the mechanical shockwaves.
8. The process according to claim 1 wherein the biofilm comprises
one or more infectious microorganisms selected from the group
consisting of bacteria, fungi, protozoa, archaea, algae and
microscopic parasites, an antibiotic-resistant microorganism,
methicillin-resistant Staphylococcus aureus, antibiotic-resistant
Staphylococcus aureus, antibiotic-resistant alpha-hemolytic
streptococci, antibiotic-resistant Streptococcus pneumoniae,
antibiotic-resistant Haemophilus influenzae, antibiotic-resistant
coagulase-negative Staphylococci, aspergillus, candida and
penicillium families, mycoplasma, alternaria, Chlamydia,
antifungal-resistant aspergillus, antifungal-resistant candida and
antifungal-resistant penicillium families, antifungal-resistant
mycoplasma, alternaria and antifungal-resistant Chlamydia.
9. The process according to claim 1 wherein the first step
comprises impinging a pulsed laser beam on to an ionizable target
to generate non-convergent pulses of mechanical shockwaves.
10. The process according to claim 9 wherein the first step
comprises pulsing the laser beam impinged on the target with one or
more pulse characteristics selected from the group consisting of a
pulse width in the range of from about 2 ns to about 20 ns, a pulse
rate of from about 0.5 Hz to about 200 Hz, a pulse energy in a
range of from about 2 mJ to about 15 mJ of energy per pulse, and a
fiber-to-target distance in the range of from about 0.7 to about
1.5 mm.
11. The process according to claim 1 wherein the antimicrobial
treatment comprises one or more steps selected from the group of
steps consisting of: applying to the biofilm a dosage of light
having a wavelength of from about 400 nm to about 1500 nm; applying
to the biofilm a dosage of light having a wavelength in the range
of from about 600 nm to about 1200 nm; applying to the biofilm a
dosage of light having a wavelength in the range of from about 800
nm to about 1200 nm and the light dosage is applied without
applying colorant or photosensitizer material to the treatment
site; applying to the biofilm a dosage of light having a wavelength
in the range of from about 850 nm to about 950 nm and the light
dosage is applied without applying colorant or photosensitizer
material to the treatment site; and applying to the biofilm a
dosage of light having a wavelength in the range of from about 400
nm to about 700 nm together with a photosensitizer material
selected to absorb the dosage of light.
12. The process according to claim 1 wherein the light dosage is
applied at an energy of from about 1 mW to about 200 mW for a
duration sufficient to deliver from about 0.2 to about 20 Joules of
energy.
13. The process according to claim 1 wherein the light dosage is
applied at an energy intensity of from about 10 mW to about 100 mW
for a duration sufficient to deliver from about 2 to about 10
Joules.
14. The process according to claim 1 wherein the treatment site
comprises a sinus or posterior nasal site, the biofilm being
present at the sinus or posterior nasal site and the second step
comprises flooding or both nasal cavities with a diffuse
antimicrobial dosage of light.
15. The process according to claim 14 wherein the second step
comprises applying a photosensitizing colorant to the anterior
nasal cavity to sensitize infectious microorganisms present in the
anterior nasal cavity to the microorganism-reducing light.
16. The process according to claim 15 comprising applying the light
dosage of microorganism-reducing light to each nasal vestibule of
the mammalian host.
17. The process according to claim 15 comprising inserting a
light-diffusing nasal dilator through a naris of the mammalian host
to dilate the nostril of the mammalian host and delivering the
light dosage through a fiber optic tip located within the nasal
dilator and through the nasal dilator to the anterior nasal cavity
of the mammalian host.
18. The process according to claim 1 wherein the treatment site
comprises one or more treatment sites selected from the group
consisting of: otolaryngological sites; middle ear cavities;
pharyngal sites; tonsillar sites; dental sites; periodontal sites;
toenails; fingernails; wound closure devices and materials;
sutures; implant sites; cardiac implant sites; endovascular implant
sites; orthopedic implant sites; gynecological implant sites;
intrauterine device sites; urologic implant sites and urinary
catheter sites.
19. The process comprising repetition of a process according to
claim 1 at one or more intervals of from about 1 to about 7
days.
20. The process of claim 1, wherein the disruption caused by the
mechanical shockwaves further comprises tearing one or more pieces
of the biofilm away from residual biofilm at the treatment
site.
21. The process of claim 1, wherein the disruption caused by the
mechanical shockwaves further comprises tearing one or more pieces
of the biofilm away from the treatment site.
22. The process of claim 1, wherein the disruption caused by the
mechanical shockwave further comprises breaking up the biofilm into
pieces.
23. The process of claim 1, wherein the disruption further
comprises breaking up the biofilm into planktonic cells.
24. The process of claim 1, wherein the disruption caused by the
mechanical shockwave further comprises substantially dislodging the
biofilm from its host structure without causing visible damage to
the host structure.
25. The process of claim 24, where the host structure is body
tissue of a patient.
26. The process according to claim 1 wherein the antimicrobial
treatment comprises applying to the biofilm a dosage of light
having a wavelength in the range of from about 800 nm to about 1200
nm.
27. The process according to claim 26, wherein the light dosage is
applied without applying colorant or photosensitizer material to
the treatment site.
28. The process according to claim 1, wherein the antimicrobial
treatment comprises applying to the biofilm a dosage of light
having a wavelength in the range of from about 850 nm to about 950
nm.
29. The process according to claim 28, wherein the light dosage is
applied without applying colorant or photosensitizer material to
the treatment site.
Description
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
(Not applicable.)
The present invention relates to processes and systems for treating
biofilms resident in mammals and provides processes and systems for
treatment of undesired mammalian biofilms to control such biofilms
and to reduce the probability of the reestablishment of same.
BACKGROUND
Biofilms are ubiquitous and can be problematic. Some examples of
common biofilms include dental plaque, drain-clogging slime and the
slippery coating found on rocks in streams and rivers.
Industrial and commercial problems attributable to biofilms include
corrosion of pipes, reduced heat transfer and/or reduced hydraulic
pressure in industrial cooling systems, the plugging of water
injection jets and the clogging of water filters. In addition,
biofilms can cause significant medical problems, for example, by
infecting host tissues, by harboring bacteria that contaminate
drinking water, and by causing rejection of medical implants.
Biofilms are generally formed when bacteria and/or other
microorganisms adhere to surfaces in aqueous environments and begin
to excrete a slimy, adhesive substance that can anchor the
microorganisms to a wide variety of materials including metals,
plastics, soil particles, medical implant materials and animal
tissue.
A biofilm is often a complex aggregation of microorganisms
comprising a protective and adhesive matrix generated by excretion
of polymeric materials, for example, polysaccharides, from the
microorganisms. Biofilms are often attached to surfaces, have
structural heterogeneity and genetic diversity, and exhibit complex
community interactions. Their protective matrix and genetic
diversity mean that biofilms are often hard to destroy or otherwise
control and conventional methods of killing bacteria, such as
antibiotics, and disinfectants, are often ineffective against
biofilms.
Because the single cell microorganisms in a biofilm typically are
in an attached state, closely packed together and secured to each
other and to a solid surface, they are more difficult to destroy
than when they are in a free-floating mobile mode, as is the case
in many mammalian infections.
A number of proposals have been made for the chemical or
pharmaceutical treatment of, or regulation of, the growth of
mammalian-resident biofilms. However, as implied above, such
methods may be ineffective or subject to resistance or both, or may
have other drawbacks commonly associated with pharmaceuticals such
as systemic action and side effects.
Some suggestions for treatment of biofilms in humans appear in the
patent literature. For example, Bornstein U.S. Patent Application
Publication No. 2004/0224288 (referenced "Bornstein" herein)
discloses a system and process for thermolytic eradication of
bacteria and biofilm in the root canal of a human tooth employing
an optical probe and a laser oscillator.
Also, Hazan et al. U.S. Patent Application Publication No.
2005/0261612 discloses a method for decreasing materials such as
biofilm attached to a mammalian body which method includes
attaching a nanovibrational energy resonator device onto an
external or internal area of the body.
Oxley et al. "Effect of ototopical medications on tympanostomy tube
biofilms." Laryngoscope. 2007 October; 117(10):1819-24 describes
experiments to examine the effect of ototopical medications on
biofilms on fluoroplastic tympanostomy tubes. Reportedly, microbial
activity in colony forming units (CFU) was decreased after three
weeks. However, despite the treatment, the biofilm was not
eradicated but continued to grow. The authors conclude that
infectivity of the biofilm can be temporarily neutralized by
antibiotic ototopicals and that the biofilm may progress despite
treatment.
International patent publication No. WO 00/67917 describes a method
for permeabilizing biofilms using stress waves to create transient
increases in the permeability of the biofilm. As described, the
increased permeability facilitates delivery of compounds, such as
antimicrobial or therapeutic agents into and through the biofilm,
which agents are apparently to be employed to treat the
biofilm.
Desrosiers et al. "Methods for removing bacterial biofilms: in
vitro study using clinical chronic rhinosinusitis specimens." Am J
Rhinol. 2007 September-October; 21(5):527-32 describes an in vitro
study on removed biofilms from bacterial isolates obtained from
patients with refractory chronic rhinosinusitis. As described, the
biofilm was treated with both static and pressurized irrigation and
a citric acid/zwitterionic surfactant. According to the authors,
the pressurized treatment employing irrigant and a surfactant can
disrupt the biofilms tested.
Notwithstanding the foregoing proposals, it would be desirable to
have new processes and treatments for treatment of biofilms
resident in or on mammalian sites.
The foregoing description of background art may include insights,
discoveries, understandings or disclosures, or associations
together of disclosures, that were not known to the relevant art
prior to the present invention but which were provided by the
invention. Some such contributions of the invention may have been
specifically pointed out herein, whereas other such contributions
of the invention will be apparent from their context. Merely
because a document may have been cited here, no admission is made
that the field of the document, which may be quite different from
that of the invention, is analogous to the field or fields of the
present invention. Nor is any admission made that the document was
published prior to, or otherwise predates, applicant's
invention.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a combination
two-step mammalian biofilm treatment process. The combination
two-step process can comprise a first step of dispersing an
undesired biofilm present at a treatment site in or on a mammalian
host by mechanically shockwaves disrupting the biofilm and a second
step. The second step can comprise applying an antimicrobial
treatment to the mammalian host to control possible infection
related to biofilm dispersed in the first step or to residual
biofilm at the treatment site. Desirably, the second step is
performed within a limited time period after the first step.
The processes of the invention can comprise one or more additional
steps performed before the first step, after the second step or
between the steps, if desired, for example a diagnostic step to
identify the presence of a biofilm and optionally to biopsy and
culture the biofilm to identify one or more microorganisms that are
present.
By applying an antimicrobial treatment to control possible
infection related to fragments or components of the biofilm that
may have been dispersed in the first step the invention provides,
in this aspect, a comprehensive mammalian biofilm process which
offers the possibility of destroying or debilitating an existing
biofilm and of reducing the probability of reestablishment or
regrowth of the biofilm.
Desirably, the limited time period between steps is relatively
short, for example about 48 hours, about 24 hours, about 3 hours,
about 1 hour, about 30 minutes or about 10 minutes. In general, it
can be expected that the more quickly the second step is performed,
the more effective it will be in controlling possible reemergence
of the biofilm.
The second, antimicrobial treatment step can be effected in any one
of a variety of ways, for example by applying an antimicrobial
dosage of light to the treatment site or by local or systemic
administration of an antibiotic material to the mammalian host.
Other suitable antimicrobial treatments will be or become apparent
to a person of ordinary skill in the art.
Employing light, the second step can comprises diffusing the
antimicrobial dosage of light onto the treatment site and in the
vicinity of the treatment site and if desired can include applying
an antimicrobial dosage of light to at least one other site on or
in the mammalian host mammalian host that is subject to receiving
material dispersed from the biofilm in the first step. Also, the
antimicrobial dosage of light can reduce or otherwise control at
least one species of the microorganisms in the biofilm.
Conveniently, infrared wavelengths of light can be employed for the
antimicrobial dosage of light, optionally without use of a
photosensitizer. However, visible energy wavelengths can be
employed, if desired, optionally with use of a photosensitizer.
The biofilm can comprise matter foreign to the mammalian host, for
example non-beneficial microorganisms and their exudates or other
products, and the first step can comprise reducing the mass of,
disrupting, attenuating or destroying the biofilm by the
application of laser-generated mechanical shockwaves.
Usefully, the first step can comprise directing the mechanical
shockwaves toward the biofilm at the treatment site. Also, the
first step can comprise oscillating the biofilm by the application
of the mechanical shockwaves.
Other methods can also be employed to perform the first step. For
example, the first step can comprise mechanically disrupting the
biofilm by performing one or more steps selected from the group
consisting of applying laser-generated mechanical shockwaves to the
biofilm, irrigating the treatment site; applying pressurized liquid
to the biofilm; applying suction to the biofilm, applying sonic
energy to the biofilm, applying ultrasonic energy to the biofilm;
mechanically scraping or abrading the biofilm, and applying
vibrations from a vibrational resonator device to the biofilm.
The biofilm can be attached to the treatment site, for example by
microorganism exopolysaccharides, and the first step can comprise
tearing one or more pieces of the biofilm away from residual
biofilm at the treatment site or from the treatment site by
applying the mechanical shockwaves.
Mammalian biofilms are often, or usually, undesired, and can
sometimes lead to medical complications if not treated effectively.
Accordingly, useful embodiments of the invention provide a simple
and effective shockwave applicator that can be employed to disperse
and help control internal or external mammalian treatment sites
where biofilms are present. Internal treatment sites can be
accessed via bodily cavities, for example the nostrils, or
subcutaneously, employing a catheter, trocar or the like, or in
other ways. A cooperative light applicator can be similarly
tailored to apply an antimicrobial dosage of light to the targeted
treatment site to provide a comprehensive biofilm treatment system
designed to debilitate and reduce recurrence of one or more
biofilms harbored at the treatment site. The light applicator can
be configured for subcutaneous, catheter, trocar, nostril or other
delivery of an antimicrobial dosage of light according to the
nature of the desired treatment site.
In another aspect, the present invention provides a biofilm
treatment system which can be used for performing a process
according to the invention, or for other purposes, if desired. The
biofilm treatment system can comprise a shockwave applicator
configured to apply the mechanical shockwaves to the biofilm and a
light applicator comprising a light source, the light applicator
being operable to apply an antimicrobial dosage of light to the
treatment site.
Shockwaves or pressure pulses to be applied to the treated biofilm
by the shockwave applicator can be generated using light energy,
for example, light energy output by a laser, or by other suitable
means, or the shockwaves can be generated in another suitable
manner.
Any suitable shockwave applicator can be employed. If desired, the
shockwave applicator can be configured to output shockwaves in a
shockwave pattern extending forwardly of the distal end of the
shockwave applicator to facilitate directing the shockwaves toward
the treatment site.
One exemplary shockwave applicator useful in the practice of the
invention comprises an ionizable target for transducing laser
energy into shockwaves and an optical fiber extending along the
shockwave applicator. The optical fiber can have a distal end
positioned adjacent the ionizable target and can be connectable
with a pulsed laser energy source to receive pulses of laser energy
from the laser energy source and discharge the pulses of laser
energy from the distal end of the optical fiber to impinge on the
ionizable target, thereby outputting shockwaves.
Also, any suitable light source can be employed for the light
applicator. Usefully, the light source can be capable of outputting
light at a wavelength in a range of from about 400 nm to about 1500
nm. For example, the light source can be capable of outputting
infrared light at a wavelength in a range of from about 850 nm to
about 950 nm. The light source can comprise a laser, a laser diode,
a light-emitting diode, a gas discharge lamp, a flash lamp or a
high intensity pulsed light.
While the invention is not limited by or dependent upon any
particular theory, it appears from such experiments that the
shockwaves employed may be sufficiently powerful to break up a
biofilm, and possibly dislodge it from its support structure,
without causing visible damage to the underlying tissue, implant or
other host structure. Also, the shockwave applicator can propagate
little or no laser energy externally of the instrument. The
shockwave applicator can include means for irrigation of the
treatment site, or both, to remove detritus from the shockwave
applicator and/or the treatment site, if desired. An aqueous fluid
can be employed for irrigation. Optionally, the aqueous fluid can
be pulsed.
Biofilms that can be treated by a process according to the
invention may be resident or on or at any of a variety of
anatomical sites and include biofilms secured to the treatment site
by polysaccharide material. The biofilms can comprise one or more
microorganisms such for example as bacteria, fungi, protozoa,
archaea, algae and/or microscopic parasites.
It is believed that shockwaves generated by certain shockwave
applicator embodiments of the invention can oscillate some biofilms
resident on various substrates and cause pieces of the biofilm to
tear away. In some cases a biofilm can be more or less completely
removed from its site of residence.
The invention includes mammalian host implants cleaned of biofilm
by a treatment process according to the invention.
In another aspect, the invention provides a new use of a biofilm
treatment system comprising a shockwave applicator including an
ionizable target for transducing laser energy into shockwaves and
an optical fiber having a distal end positioned adjacent the
ionizable target and being connectable with a pulsed laser energy
source to receive pulses of laser energy from the laser energy
source and discharge the pulses of laser energy from the distal end
of the optical fiber to impinge on the ionizable target to generate
and output shockwaves for treating mammalian resident biofilm by
application of the shockwaves to the biofilm and comprising a light
applicator for applying an antimicrobial dosage of light energy to
a mammalian treatment site harboring the biofilm.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
Some embodiments of the invention, and of making and using the
invention, as well as the best mode contemplated of carrying out
the invention, are described in detail herein and, by way of
example, with reference to the accompanying drawings, in which like
reference characters designate like elements throughout the several
views, and in which:
FIG. 1 is a schematic view of laser generation of shockwaves from
the distal tip of a shockwave applicator useful in the practice of
the invention;
FIG. 1A is a graph showing schematically the effects of various
laser treatments that are generally obtainable at different power
densities, energy densities and application times;
FIG. 2 is a perspective view of an embodiment of a shockwave
applicator according to one embodiment of the invention which can
be useful as a shockwave applicator for applying shockwaves to
treat biofilms at sinus and other locations;
FIG. 3 is a front view of the shockwave applicator shown in FIG.
2;
FIG. 4 is section on the line 4-4 of FIG. 3;
FIG. 5 is an enlarged view of the tip of the shockwave applicator
shown in FIG. 4;
FIG. 6 is a view similar to FIG. 4 of another embodiment of
shockwave applicator component according to the invention;
FIG. 7 is a schematic perspective view of an embodiment of a light
applicator according to one embodiment of the invention which can
be useful for applying a dosage of antimicrobial light to a
treatment site harboring a biofilm or biofilm remnants; and
FIG. 8 is an enlarged view of the nasal light applicator shown in
FIG. 5, showing some internal structure thereof.
DETAILED DESCRIPTION OF THE INVENTION
U.S. patent application Ser. No. 12/139,295, the disclosure of
which is incorporated by reference herein, describes and claims a
process for treating biofilms wherein shockwaves are applied to a
biofilm to disperse it. In vitro data described in that application
demonstrate a shockwave treatment causing a biofilm to oscillate,
tearing and disintegrating the biofilm and substantially removing
the biofilm from a site of attachment such as a bundle of sutures,
an orthopedic screw or a tympanostomy tube.
The present invention provides a comprehensive process for treating
biofilms which aims to both disperse a biofilm present at a
treatment site and to reduce the probability of the biofilm
reforming or regenerating. As described herein the invention
includes a two-step mammalian biofilm treatment process comprising
dispersing an undesired biofilm present at a treatment site in or
on a mammalian host by applying laser-generated mechanical
shockwaves to the biofilm and a second step of applying an
antimicrobial treatment to the mammalian host to control possible
infection related to biofilm dispersed in the first step.
Desirably, the second step can be performed soon after the first
step. In another embodiment of the invention the second step can be
performed more or less simultaneously with the first step. In
general, the shockwave treatment processes described in patent
application Ser. No. 12/139,295 can be employed for practicing the
first step of the processes described herein and shockwave
applicators or instruments are useful as shockwave applicators in
system aspects of the present invention. Other processes and
devices can alternatively be used for performing the first step, as
is described herein or as will be known or apparent to a person of
ordinary skill in the art, in light of this disclosure, or will
become known or apparent in the future, as the art develops
International Publication No. WO 2008/067,361, the disclosure of
which is incorporated by reference herein describes light
application methods and light applicators which can be employed in
practicing the second step of process aspects of the present
invention or as light applicators in practicing system aspects of
the present invention.
The antimicrobial treatment can comprise any suitable measure for
example administration or application of an antimicrobial dosage of
an antibiotic substance or composition or of light at a suitable
wavelength.
For treatment of biofilms that potentially may comprise
antibiotic-resistant microbes, the invention provides a biofilm
treatment system comprising a mechanical shockwave applicator to
disperse the biofilm and a light applicator to provide an
antimicrobial treatment to control possible residual biofilm at the
treatment site or dispersed biofilm fragments or organisms, and to
inhibit reestablishment or regeneration of the biofilm at the
treatment site or elsewhere.
Desirably, in some cases, light energy can be employed at infrared
wavelengths to provide a simple antimicrobial treatment not
requiring use of photosensitizers, stains, colorants or the like at
the target site.
The light energy can include ultraviolet wavelengths, if desired.
However, considerable care will likely be needed to avoid tissue
damage when employing ultraviolet light energy. Thus, the invention
also provides treatment processes which avoid use of ultraviolet
light.
If desired an antibiotic compound or composition can be
administered systemically or locally, or both systemically and
locally, to provide an antimicrobial treatment which is alternative
or adjunctive to the use of light, where antibiotic resistance is
not a concern.
The invention can provide a biofilm treatment system comprising a
shockwave applicator and a light applicator that are cooperative to
provide a comprehensive treatment of a particular bodily site
harboring a biofilm or of a biofilm-implicated condition. For
example, the shockwave applicator can have an output proximally
mounted on an extended reach needle or the like to access internal
treatment sites such as a sinus cavity through a body opening such
as a nostril and the light applicator can be configured to apply a
suitable dosage of light energy through the same opening, the
nostril to reach the same treatment site, the sinus cavity.
Desirably the light applicator can also spread the light around the
nostril and the posterior nasal cavity, being locations where
dispersed biofilm fragments could potentially lodge and reestablish
themselves. In another example, both the shockwave applicator and
the light applicator can both be adapted for insertion into a body
opening, for catheter delivery, or trocar use to access a treatment
site subcutaneously or through a bodily lumen, for example the
vasculature or to access a bodily cavity, or in other suitable
manner.
The shockwave applicator can be capable of outputting high energy
shockwave pulses of short duration and directing them to a specific
structure or area, for example a biofilm or an anatomical,
prosthetic or implant structure supporting the biofilm.
Surprisingly, high energy shockwave pulses can be applied and a
biofilm can be broken up, dispersed or destroyed with little if any
damage to underlying or surrounding tissue. The light applicator
can be capable of being employed to spread light if desired,
flooding or bathing an area including and extending beyond the
footprint of the biofilm to reach other locales where biofilm
fragments may be present and target these areas with an
antimicrobial dosage of light.
Biofilms can form in mammalian hosts when bacteria adhere to a wet
surface and begin to excrete a slimy, glue-like substance that can
anchor the bacteria to tissue or medical implants. Such biofilms
can comprise many types of bacteria, fungi, debris and corrosion
products. Biofilms encountered in the human or other mammalian body
generally comprise matter which is foreign to the mammalian host.
Generally, biofilms do not comprise host tissue and are not useful
components of the mammalian host. Thus, embodiments of the
invention may apply treatments to host tissue on which biofilm
resides or which are in the vicinity of biofilms but generally do
not aim to change or modify the host tissue or other host structure
subject to treatment. One embodiment of the invention comprises
controlling or attenuating biofilm foreign matter while leaving
host tissue intact. Useful embodiments of the invention target
biofilms which may actively or passively adversely affect normal
functioning of the mammalian host.
Non-living surfaces in the body, for example catheters, contact
lenses, artificial joints and other medical devices may be more
prone to biofilm formation than living tissue. However, biofilms
can also grow on living tissue, and may cause diseases such as
endocarditis, lung, dental, sinus, ear and other infections. For
example, it is believed that biofilms may play an etiologic role in
chronic otolaryngologic infections. Therapeutic methods designed to
treat acute infections caused by surface or floating (planktonic)
microorganisms may be found to be ineffective for chronic
infections when biofilms are present.
Bacteria can adhere to solid surfaces and excrete a slimy, slippery
coat with structured features. The resulting adherent mass can be
referred to as a bacterial biofilm. The formation of biofilm
structure occurs in multiple stages. First the bacteria may attach
to a convenient, usually wet, surface. The attachment may be
strengthened by a polymeric matrix adhering densely to the surface,
and an aggregation of micro colonies occurs. The environment can
provide growth and maturation for the biofilm which becomes an
organized structure. Finally, during its mature phases, the biofilm
may detach, disperse or embolize to perform the same cycle in
adjacent or distant areas.
The composition of a biofilm can comprise, for example, about 15%
by weight of bacteria cells and about 85% by weight of `slime`. The
slimy environment also appears to protect the bacteria from natural
host defenses such as inflammatory cells, antibodies and
antimicrobial treatments. As the biofilm cells consume nutrients
from surrounding tissue and fluids, nutrient gradients develop
until bacteria near the center or centers of the biofilm become
starved and go into quiescent state. It is speculated that this
dormancy may partially explain the resistance often displayed by
biofilm bacteria to antibiotics which are effective against rapidly
growing bacteria in standard tests. The biofilm bacteria survive in
a matrix rich in extracellular polymeric substances ("EPS" herein)
including polysaccharides, nucleic acids and proteins providing a
protective and nutritious environment to the microorganisms.
Some examples of virulent bacteria that may be found in biofilms
treatable by the processes and systems of the invention, with
diseases with which they are associated indicated in parenthesis,
are: Pseudomonas aeruginosa (cystic fibrosis); Staphylococcus
aureus (osteomyelitis); Proteus vulgaris (pyelonephritis);
Streptococcus viridans (endocarditis); culture-negative
prostatitis; and Haemophilus influenzae (otitis media).
It is also believed that a biofilm can have a complex morphology
comprising communication channels in which cells in different
regions of the biofilm exhibit different patterns of gene
expression. It may have a three dimensional architecture with open
channels that allow the transport of nutrients into the biofilm.
Furthermore, bacteria in biofilms may communicate through quorum
sensing molecules that can coordinate and up-regulate virulence
factors when cells became starved. Quorum sensing, or exchange of
molecules, genes, DNA and free communication between cells, can
provide the bacteria within the biofilm a resistant and protective
environment. Known anti-bacterial agents may require a hundred- or
thousand-fold `normal` antibiotic dosage to be effective against
such resistant biofilm structures; which is not feasible to
administer systemically owing to toxicity.
Biofilms can provide a mechanism for microorganisms to survive
extreme temperature changes, radiation or mechanical trauma.
Antibiotics may eradicate planktonic (floating or drifting)
microorganisms, and possibly also surface bacteria on a biofilm
without damaging bacteria protected within the polymer matrix. This
understanding may point to a role of biofilms in the etiology of
chronic infections with acute exacerbations. Some examples in
otolaryngology include chronic rhinosinusitis, chronic otitis
media, adenoiditis and cryptic tonsillitis. A given condition may
be aggravated by the presence of a prosthetic, implantable device
or catheter for example a tympanostomy tube, a tracheotomy tube, a
cochlear implant, a stent, packing material or a foreign body.
Biofilms preferentially form in grooves, depressions, pockets and
other surface discontinuities on host-resident medical devices and
implants. Biofilms can also form between or on the fibers of
sutures, on cuffs and in the mesh-like structures of knitted or
woven grafts. The literature reports having found a dense biofilm
in the surface depressions of a cochlear implant removed from a
patient with an intractable infection. These and other sites where
biofilms are attached, resident or supported can constitute
treatment sites to be subjected to shockwave treatments in
embodiments of the processes of the present invention.
Not all biofilms are pathogenic. However even non-pathogenic
biofilms can create an inflammatory reaction in surrounding host
tissue and may cause collateral damage through cytotoxic,
proteolytic, and proinflammatory effects. These effects may cause
localized tissue reactions and recurrent infections. Sometimes, the
host response to a biofilm can result in severe and sustained
inflammation. For example, in diseases such as cystic fibrosis and
gingivitis, if the neutrophils fail to engulf the bacteria inside
biofilms, they may degranulate and damage host tissues.
The processes of the invention described herein usefully can be
employed in the treatment of biofilms resident in mammals,
including in particular, humans. In addition, these processes can
be applied to treatment of non-human mammals including, for
example, horses, cattle, sheep, llamas, husbanded animals, pets
including dogs and cats, laboratory animals, for example, mice,
rats and primates, animals employed for sports, breeding,
entertainment, law enforcement, draft usage, zoological or other
purposes, if desired. The processes and devices of the invention
are not limited by the theories of biofilm formation and structure
described herein or by any other theories.
Processes according to the invention can be employed to treat
biofilms resident at, adhered to, or otherwise present at any of a
variety of anatomical sites, including any one or more sites
selected from the group consisting of otolaryngological sites;
nasal, sinus, and middle ear cavities; pharyngal, tonsillar, dental
and periodontal sites; toenails, fingernails and their environment;
wound closure devices and materials, sutures, sites on cardiac
implants, endovascular implants, orthopedic implants, gynecological
implants, intrauterine devices, urologic implants, urinary
catheters, therapeutic and other implants as will be or become
apparent to a person of ordinary skill in the art. The invention
provides treatment systems adapted to treat a biofilm present at
any one or more of the foregoing sites by a process according to
the invention.
The invention includes embodiments wherein the biofilm can be
present at a treatment site selected from the group consisting of
the sinuses, the sinuses accessible via the nasal cavity, the
frontal, ethmoidal, sphenoidal and maxillary sinuses, otological
sites, upper nasal, and middle ear cavities.
The biofilm treatment processes of the invention can provide a
comprehensive approach to complete or partial elimination of,
attrition of, removal or reduction of, destruction of or other
desired control of, or biofilm resident in or on a host mammal, in
particular, a human being, and prevention of its recurrence.
Processes according to the invention can treat undesired biofilms
which may cause the host to be symptomatic and in some cases can
lead to medical complications.
As summarized above the invention provides biofilm treatment
processes which comprise mechanically disrupting or a biofilm
resident at a treatment site on or in a mammalian host, followed by
an antimicrobial treatment.
Mechanical disruption can comprise a process which physically
breaks up a biofilm, disturbs, disrupts or subverts the protective
layer or layers of the biofilm which may inhibit antimicrobial
treatments or otherwise physically treats the biofilm to render the
microbial components of the biofilm more susceptible to reduction
or attenuation by an antimicrobial such as a pharmaceutical agent
or antimicrobial radiation, which radiation treatment optionally
can be enhanced by a sensitizer.
As described herein mechanical disruption can be effected in any
one or more of a variety of ways. By way of example, the
application of laser-generated mechanical shockwaves to the biofilm
is described in detail herein.
Alternative methods for mechanically disrupting the biofilm include
irrigating the treatment site; applying pressurized liquid to the
biofilm; applying suction to the biofilm, applying sonic energy to
the biofilm, applying ultrasonic energy to the biofilm;
mechanically scraping or abrading the biofilm, applying vibrations
from a vibrational resonator device to the biofilm and other
methods as will be known or apparent to a person of ordinary skill
in the art, in light of this disclosure, or will become known or
apparent in the future, as the art develops.
Irrigating the treatment site can be effected in any suitable
manner, for example by manipulating a probe or other suitable
instrument coupled to a source of saline, or other suitable
pressurized fluid, generally, but not necessarily, a liquid, to
direct a flow, optionally a pressurized jet of irrigation fluid at
the biofilm. If desired, the fluid flow can be moved around to
impact different parts of the biofilm by suitable manipulation of
the irrigation instrument.
Alternatively, or in addition, suction can be to the biofilm, in a
comparable manner, employing a manipulatable instrument coupled to
a suction source.
If desired, sonic or energy can be applied to the biofilm employing
a sonic energy generating device. The sonic energy can be
transmitted from the sonic energy generating device, radiatively or
conductively, or in another suitable manner. For example, sonic
energy can be output from the generating device and directed at the
biofilm treatment site to travel through an intervening fluid
medium or fluid media, to the biofilm treatment site.
Alternatively, the generating device can be contacted with a
suitable available portion of the patient's anatomy and conducted
through the patient's skin, bone, tissue, or other anatomy to the
biofilm treatment site.
Ultrasonic, or other vibrational or microvibrational energy can be
applied to the biofilm in a comparable manner to that described for
sonic energy, employing a suitable ultrasonic, or other vibrational
or microvibrational energy generating device which can optionally
be a resonator device or other suitable energy generating
device.
Mechanically scraping or abrading the biofilm, can be effected by
suitable manipulation of a probe configured with a suitable scraper
or abrader tip. Optionally, the probe tip can have a sharp, dull or
blunt blade or the like for scraping, or a suitably configured
abrasive surface, or another suitable configuration.
In any mechanical disruption method, if desired, and if
practicable, the applied disruptive force can be moved around the
biofilm or the biofilm treatment site to impact different parts of
the biofilm by suitable manipulation of the instrument or other
device employed to apply the disruptive force.
In one embodiment of the invention, employing shockwaves, the
shockwaves generated are non-convergent shockwaves and the process
can comprise directing the non-convergent shockwaves on to the
biofilm resident at the treatment site.
Biofilms can comprise a wide variety of microorganisms, for
example, one or more microorganisms selected from the group
consisting of an antibiotic-resistant microorganism,
methicillin-resistant Staphylococcus aureus, antibiotic-resistant
Staphylococcus aureus, antibiotic-resistant alpha-hemolytic
streptococci, antibiotic-resistant Streptococcus pneumoniae,
antibiotic-resistant Haemophilus influenzae, antibiotic-resistant
coagulase-negative Staphylococci, aspergillus, candida and
penicillium families, mycoplasma, alternaria, Chlamydia,
antifungal-resistant aspergillus, antifungal-resistant candida and
antifungal-resistant penicillium families, antifungal-resistant
mycoplasma, alternaria and antifungal-resistant Chlamydia.
The first, shockwave application step of a process according to the
invention can comprise impinging a pulsed laser beam on to an
ionizable target to generate non-convergent pulses of mechanical
shockwaves. For example, the first step can comprise pulsing laser
energy impinged on the target to have one or more pulse
characteristics selected from the group consisting of a pulse width
in the range of from about 2 ns to about 20 ns, a pulse rate of
from about 0.5 Hz to about 200 Hz, a pulse energy in a range of
from about 2 mJ to about 15 mJ of energy per pulse, and a
fiber-to-target distance in the range of from about 0.7 to about
1.5 mm.
The antimicrobial treatment comprises applying to the biofilm a
dosage of light having a wavelength of from about 400 nm to about
1500 nm, for example a dosage of light having a wavelength in the
range of from about 600 nm to about 1200 nm.
Another example of the antimicrobial treatment comprises applying
to the biofilm a dosage of light having a wavelength in the range
of from about 800 nm to about 1200 nm and the light dosage is
applied without applying colorant or photosensitizer material to
the treatment site.
A further example of the antimicrobial treatment comprises applying
to the biofilm a dosage of light having a wavelength in the range
of from about 850 nm to about 950 nm and the light dosage is
applied without applying colorant or photosensitizer material to
the treatment site.
A still further example of the antimicrobial treatment comprises
applying to the biofilm a dosage of light having a wavelength in
the range of from about 400 nm to about 700 nm and applying to the
biofilm a colorant selected to absorb the dosage of light or a
photosensitizer material.
The light dosage can be applied at an energy of from about 1 mW to
about 200 mW for a duration sufficient to deliver from about 0.2 to
about 20 Joules of energy. For example, the light dosage can be
applied at an energy intensity of from about 10 mW to about 100 mW
for a duration sufficient to deliver from about 2 to about 10
Joules.
The treatment site can comprise a sinus or posterior nasal site or
other sinonasal site, and the biofilm can be present at the sinus
or posterior nasal site and the second step comprises flooding the
nasal cavities with a diffuse antimicrobial dosage of light.
Where the treatment site comprises a sinonasal site, the second
step can comprise applying an antimicrobial light dosage to each
anterior nasal cavity of the mammalian host and, optionally,
depending upon the wavelength of light employed, applying a
colorant to the anterior nasal cavity to sensitize infectious
microorganisms present in the anterior nasal cavity to the
microorganism-reducing light.
The light dosage of microorganism-reducing light can be applied to
each nasal vestibule of the mammalian host. The antimicrobial
treatment can comprise inserting a light-diffusing nasal dilator
through a naris of the mammalian host to dilate the nostril of the
mammalian host and delivering the light dosage through a fiber
optic tip located within the nasal dilator and through the nasal
dilator to the anterior nasal cavity of the mammalian host.
The biofilm treatment process can be repeated as desired, for
example at one or more intervals of from about 1 to about 7
days.
The biofilm treatment system can comprise a light applicator having
a light source comprising an optical fiber and a diffuser to
diffuse light emitted from the optical fiber. The light applicator
comprises a hand piece to enable a user to manipulate the light
applicator and the hand piece can be removably attachable to the
optical fiber.
The light applicator can be insertable into a bodily cavity of the
mammalian host to apply the light dosage within the bodily
cavity.
In one example, the light applicator is configured for applying
light to the interior nasal anatomy of the mammalian host and
comprises a light output member to deliver light within the nose
and a hollow light-transmissive, light diffusing nasal dilator
insertable through a naris of the treatment mammalian host to
dilate the nose, wherein the light output member can be
accommodated in the hollow interior of the nasal dilator to deliver
light to the interior nasal anatomy through the nasal dilator.
A shockwave applicator useful in practicing process aspects of the
invention or in a biofilm treatment system according to the
invention can be capable of generating pulsed laser energy having
one or more pulse characteristics selected from the group
consisting of a pulse width in the range of from about 2 ns to
about 20 ns, a pulse rate of from about 0.5 Hz to about 200 Hz, a
pulse energy in a range of from about 2 mJ to about 15 mJ of energy
per pulse.
One example of a suitable shockwave applicator comprises a needle
portion supporting the ionizable target and optical fiber, the
needle portion comprising an elongated proximal section to reach
into a bodily cavity and a distal tip disposable in a bodily cavity
to output shockwaves generated by the shockwave applicator.
The needle portion can comprise a curved section between the distal
tip and the elongated proximal section. The curved section can
orient the distal tip to address a treatment site, the distal tip
optionally being oriented at an angle in the range of from about
40.degree. to about 60.degree. or in the range of from about
10.degree. to about 25.degree. to the longitudinal axis of the
proximal section. The distal tip can comprise a distally elongated
straight section and a generally triangular cross-section along the
length of the distally elongated straight section.
The distally elongated straight section of the distal tip comprises
a distally elongated flat or convex target surface and the
shockwave applicator optical fiber comprises a fiber end disposed
to impinge laser energy on the target surface to generate
shockwaves and wherein the target surface is oriented to project
the shockwaves in a limited geometric volume forwardly of the
distal tip and angled to the axis along the distal tip straight
section on the same side of the axis as proximal section. And the
distally elongated straight section can comprise a heat sink. Other
configurations will be apparent for application to other host
treatment sites.
If desired, a biofilm treatment system according to the invention
can further comprise an endoscope for viewing the treatment site,
the shockwave applicator and endoscope being configured for the
application of shockwaves to the treatment site to be modified in
response to a view of the treatment site wherein, optionally, the
shockwave applicator and endoscope are configured for insertion
into the mammalian host to treat biofilms at non-ophthalmologic
sites.
Some embodiments of process according to the invention can comprise
controlling the biofilm non-thermolytically or by avoiding delivery
of heat to the treatment site or without applying stain to the
biofilm or according to a combination of two or all of the
foregoing parameters. In other embodiments, the process can
comprise controlling the application of shockwaves to maintain host
tissue at the treatment site intact or free of symptoms of heat or
other damage or both intact and free of symptoms of heat
damage.
In some cases a single treatment can be effective to provide
adequate destruction, disruption or dispersal of the biofilm.
Multiple passes may be employed in the course of a single
treatment. In some embodiments of the invention an individual
treatment wherein shockwaves are being applied to a biofilm can be
performed in less than five minutes and the interval during which
shockwaves are applied to the biofilm can be no more than two
minutes or, possibly, one minute. During this interval, a desired
number of shockwave pulses can be targeted at the biofilm, which
number can be in the range of from about 5 to about 100 pulses, for
example in the range of from about 10 to about 50 pulses. In some
cases such a single treatment can more or less completely disrupt,
disperse or destroy the biofilm.
The invention also includes processes wherein a biofilm infection
or infestation is treated repeatedly at intervals, for example, of
from about four hours to about a month. The treatments can, if
desired be repeated at intervals of from about 1 to about 14 days.
Treatments can be repeated until adequate control of the biofilm,
and of recurrence of the biofilm, are obtained, if desired. A
course of treatment can, for example, endure for from about two
weeks to about twelve months or for another suitable period.
The term "shockwave" as used herein is intended to include unsteady
pressure fluctuations or waves having a speed greater than the
speed of sound. Also included are pressure waves having a speed
greater than the speed of sound which comprise a disturbed region
in which abrupt changes occur in the pressure, density, and
velocity of the medium through which the pressure wave is
traveling.
The processes of the invention can employ any suitable shockwave
applicator which can apply shockwaves, pressure pulses or other
suitable non-chemical mechanical or energetic forces to mammalian
biofilms to destroy them partially or completely, without
unacceptable damage to host tissue, for example, so that the tissue
at the treatment site remains intact. The energetic forces can be
generated by laser or other photic means, piezoelectrically or in
another desired manner.
Some examples of shockwave applicators suitable for the practice of
the present invention include surgical instruments such as are
disclosed in Dodick et al. U.S. Pat. Nos. 5,906,611 and 5,324,282
(referenced as "the Dodick instrument" herein). The disclosure of
each of the Dodick et al. patents is incorporated by reference
herein. Some uses and modifications of the Dodick instrument which
also can be useful in the practice of the present invention are
disclosed in Thyzel U.S. Patent Application Publication No.
2007/0043340 (referenced as "Thyzel" herein). The disclosure of
Thyzel is also incorporated by reference herein.
As described by Dodick et al., the Dodick instrument is a
laser-powered surgical instrument that employs a target for
transducing laser energy into shockwaves. The instrument can be
used in eye surgery, particularly for cataract removal which can be
effected by tissue fracturing. The Dodick instrument can comprise a
shockwave applicator holding a surgical needle and an optical fiber
extending through a passageway in the needle. An open distal
aspiration port for holding tissue to be treated communicates with
the passageway through the needle. An optical fiber can extend
along the length of the needle and have its distal end positioned
close to a metal target supported by the instrument. Also as
described by Dodick et al., pulses of laser energy are discharged
from the distal end of the optical fiber to strike the target. The
target, which can be formed of titanium metal, is described as
acting as a transducer converting the electromagnetic energy to
shockwaves that can be directed onto tissue in an operating zone
adjacent to the aspiration port. If desired, the needle can be
flexible to enhance access to treatment sites.
As described in the literature, such laser generated shockwave
technology can be used in cataract surgery for extraction and
photolysis of the lens and for the prevention of secondary cataract
formation. The technology can be used in surgical methods which
gently break-up the cloudy lens into tiny pieces that can be
removed through an aperture of the probe. Using several hundred
pulses, resulting in high pressures the object can be cracked
efficiently with low energy deposition and without significant
temperature changes around the needle.
According to M. Iberler et al. "Physical Investigations of the
A.R.C.-Dodick-Laser-Photolysis and the Phacoemulsification", unlike
ultrasonic energy cataract treatments, this type of instrument
produces no clinically significant heat at the incision site, when
employed for cataract surgery. Apparently, the heat created within
the tip of the instrument can be dissipated by heat transport in
the solid titanium target.
Some embodiments of the present invention can employ the shockwaves
generated at the instrument's distal port, to impinge on and
destroy, attenuate, disrupt or dislodge a host-resident biofilm
attached to host tissue, to an implant surface or to another
treatment surface located in the operating zone adjacent the
shockwave applicator's distal port. The process can be performed
with or without aspiration through the shockwave applicator's
distal port or through another port in the shockwave applicator or
another device.
The shockwaves output can be directed at a biofilm or other target,
and in some embodiments of the invention can be applied in an
identifiable approximate pattern such as a circle, an ellipse or a
comparable shape, or a portion of such a pattern. The shockwaves
can be output as a non-convergent shockwave beam confined to be
directional. For example the shockwave beam can be divergent and
can have a generally conical or other suitable shape. The
divergence of the shockwave beam, defined by opposed outer edges of
the beam can be from about 0.degree. to about 90.degree. for
example from about 5.degree. to about 30.degree.. Such a
non-convergent shockwave beam can be useful for controlled
application of shockwaves on selected areas of a treatment
site.
While the invention is not limited by any particular theory, it is
believed that the application of mechanical shockwaves or other
pressure pulses will burst the cell walls of at least some of the
organisms in the treated biofilm, destroying the organisms. Unlike
chemical or pharmaceutical processes which may have little effect
on dormant organisms that may have very low metabolic rates, the
shockwaves employed are expected, in some cases, also to destroy
such dormant organisms that receive the full effect of a shockwave
output from the shockwave applicator. Destruction of organisms that
are actually or potentially resistant to antibiotics is
contemplated to be achievable, in some cases. Accordingly, in some
cases where the biofilm infection is readily accessible,
substantial elimination of the biofilm can be feasible. Multiple
treatments can be useful to obtain a desired attrition of a
particular biofilm.
Also, the treatment processes of the invention can be controlled to
be non-damaging to host tissue or to cause only modest, acceptable
damage compatible with the seriousness of the infection. This is
unlike the process described by Dodick et al. which comprises
fracturing the tissue.
Similarly, it is contemplated that the inventive treatment
processes can be performed with little, if any, pain being
inflicted on the host mammal. In the case of severe or persistent
biofilm infections, higher intensity shockwave dosages, which can
cause minor discomfort or modest pain, may be acceptable.
At sensitive treatment sites, or in other situations where more
gentle treatments are desired, less frequent repetition rates or
pressure pulses below shockwave intensity can be employed. For
gentle treatments, single pulses at desired intervals, or pulse
repetition rates in the range of from about 1 to about 10 Hz, or
other desired patterns of repetition, or mild conditions, can be
employed, if desired.
In some embodiments of the practice of the inventive biofilm
treatment process, the distal port of the shockwave applicator from
which shockwaves or other mechanical pulses are output can be
translated across the biofilm during the application of mechanical
shockwaves. Such translation can be effected by linear movement of
the shockwave applicator relatively to the biofilm, by relative
rotational movement, or by combinations of the two. Varying the
rate of translation or the pattern of translation, or both,
provides a surgeon or other operator a useful parameter for
controlling the intensity of application. For example, the
shockwave applicator can be reciprocated back and forth, with or
without rotational movements in juxtaposition to the target biofilm
and can output shockwaves in a directional beam so that the
directional shockwave beam sweeps back and forth across the target
biofilm, ablating the target biofilm progressively with each sweep.
If desired, the requisite manipulations can be visually guided
according to observation of depletion of the biofilm employing a
visual aid such as is described herein.
Other parameters the operator can adjust to help manage a treatment
are described elsewhere herein or will be or become apparent to a
person of ordinary skill in the art in light of this disclosure.
Where helpful to protect local tissue, the biofilm can, if desired,
be treated in multiple passes whereby incremental attrition or
destruction of the biofilm can be achieved.
As described in the Dodick et al. patents, the passageway in the
needle of the Dodick instrument can be used for infusion of saline
or for aspiration of saline and tissue. In practicing the present
invention, this passageway can be employed for irrigation of the
treatment site with saline or other suitable fluid or for
aspiration of the fluid and debris, including biofilm remnants
produced by application of mechanical shockwaves to the biofilm at
the treatment site. In general, it is not anticipated that tissue
fragments will be present or aspirated, although in some cases they
may be.
In various embodiment of the treatment processes of the invention,
the passageway in the shockwave applicator can be employed for
aspiration and a separate instrument can be employed for
irrigation. In other embodiments of the treatment process of the
invention, the passageway in the shockwave applicator can be
employed for irrigation and a separate instrument can be employed
for aspiration. In further embodiments of the treatment processes
of the invention, the shockwave applicator can be provided with
passageways for both irrigation and aspiration.
A process embodiment of the invention comprises slow downstream
irrigation of the fiber tip to keep it clean and to remove detritus
without the use of suction.
The laser energy pulses employed to induce the shockwaves or
pressure pulses used in the biofilm treatment processes of the
invention can be provided by any suitable laser. For example, as
described by Dodick et al., a neodymium-doped
yttrium-aluminum-garnet laser ("neodymium-YAG" or "ND:YAG") laser
providing light energy at a wavelength of 1,064 nanometers with a
pulse width of approximately 8 nanoseconds ("ns" herein) and an
absorption coefficient in water of 0.014/mm can be employed.
Alternatively, other laser types can be employed, for example, gas
lasers or solid lasers.
The laser energy pulses can be provided with any suitable
characteristics including pulse width, pulse repetition rate and
pulse energy. A pulse width or pulse duration in the range of from
about 2 ns to about 20 ns can be employed, for example from about 4
ns to about 12 ns. A pulse rate of from about 0.5 Hz to about 50
Hz, for example from about 1 Hz to about 10 Hz can be employed.
Higher pulse rates up to about 100 or 200 pulses per second can be
employed, if desired. Any suitable pulse energy can be employed,
for example, in a range of from about 2 to about 15 millijoules
("mJ") of energy per pulse. Some embodiments of the invention can
employ a pulse duration of from about 8 to about 12 nanoseconds, a
repetition rate of from about 2 to about 6 pulses per second and/or
an energy per pulse of from about 6 to about 12 millijoules.
In some cases, utilizing such parameters, from about 200 to about
800 shockwave-generating laser energy pulses can be employed to
effectively treat a biofilm or a portion of a biofilm addressed by
the distal port of the shockwave applicator, without significant
tissue or other damage. However, depending upon the area of biofilm
to be treated, more or less laser energy pulses may be effective,
for example from 5 pulses to 1500 pulses can be employed. For
example, smaller treatment sites such as the ethmoid sinus can be
effectively treated with a smaller number of pulses, for example
less than 200 pulses. Comparably, larger treatment sites, for
example a maxillary sinus can be treated with a greater number of
pulses, for example 500 or more pulses, and if the area of the site
so indicates, more than 800 pulses.
While, as noted herein, the invention is not limited by any
particular theory, FIG. 1A helps explain how a pulsed YAG laser, or
comparable laser or other energy source, can be employed in
embodiments of the present invention to generate high intensity
shockwaves of short duration that can be employed to control a
biofilm resident in a mammalian host without significant damage to
tissue or other host structure supporting or in the vicinity of the
biofilm.
FIG. 1A provides a graphic indication of the comparative effects of
a number of different therapeutic treatments comprising the
application of laser or laser-generated energy to tissue. In
general, the therapeutic effect of a particular energy treatment of
mammalian tissue and of possible collateral damage will be
functions of the nature and quantity of energy delivered and the
distribution of the energy over space and time. An excessive
concentration of energy in space and time may result in tissue
damage, for example, from undue heating.
In FIG. 1A, laser energy application time in seconds and power
density in watts/cm.sup.2 are plotted on the "X" and "Y" scales
respectively while energy density in J/cm.sup.2 is plotted on a
diagonal scale. All the scales employed are logarithmic so that
small graphic differences on each scale may correspond with
substantial quantitative differences in the energy parameters
depicted. A number of different laser energy technologies is
referenced beneath the "X" scale and their approximate time scales
are indicated.
As may be seen from FIG. 1A, in general, classical laser
technologies such as visible wavelength krypton, argon and long
pulse KTP (potassium titanyl phosphate) lasers, as well as longer
and shorter infrared lasers, employ relatively low power densities
and long application times. These technologies can have useful
applications such as for vaporization, coagulation, photodynamic
therapy and biostimulation.
More recently developed lasers such as Q-switched lasers and
short-pulse KTP lasers and the like employ relatively higher power
densities and shorter application times. These technologies can
have useful applications such as for photoablation and
photodestruction. As shown by an arrow in the upper lefthand corner
of FIG. A, a pulsed YAG laser outputting in the infrared, such as
can be employed in practicing the present invention, employs a
notably high power density, for example, in excess of 10.sup.12
watts/cm.sup.2, and a notably short application time, for example
measured in nanoseconds or less. Because the higher power density
may be applied for a quite short time, the energy density with such
a use of a pulsed YAG laser can be comparable with that of
classical lasers, namely around 10.sup.2 joule/cm.sup.2, give or
take an order of magnitude. The energy density may also depend upon
the particular geometry of the application.
The Dodick instrument can be modified as appropriate for use in any
one or more process embodiments of the present invention. If
desired, the invention can include a shockwave applicator or a
range or kit of shockwave applicators adapted for treatment of
particular treatment sites. For example, the distal end of the
shockwave applicator can be elongated to be received into a
subject's nostril for treatment of the upper nasal cavity or can be
further elongated for treatment of one or more sinus cavities. For
treatment of one or more sinus cavities, the distal end of the
shockwave applicator can be sufficiently thin and elongated to be
received into the nose and access a desired sinus cavity.
For treatment of cardiac, orthopedic, gynecologic, urologic or
other implants, the shockwave applicator can be adapted for
catheter delivery of the distal tip of the shockwave applicator to
a treatment site via a suitable blood vessel or vessels, for
example, an artery. Alternatively, the shockwave applicator can be
appropriately modified for subcutaneous delivery, for example, for
laparoscopic delivery. The invention includes biofilm treatment
processes wherein the shockwave applicator can be delivered via a
catheter, or laparoscopically, or in other suitable manner.
In some embodiments of the invention, the shockwave applicator can
comprise an inspection fiber to view the treatment site and monitor
the progress of the treatment. This capability can be useful for
treatment sites which are unexposed or concealed including internal
sites such as the upper nose and sinuses and implant surfaces. The
inspection fiber can have a distal input end disposable in the
vicinity of the applicator needle tip to survey the treatment site
and a proximal output end communicating optically with an output
device viewable by a surgeon or other operator performing the
treatment. The output device can be a video screen, an optic
member, or another viewing element. If desired, the inspection
fiber can extend through or alongside the shockwave applicator or
can comprise a separate device. Also if desired, the shockwave
applicator with the inspection fiber can be inserted into a bodily
cavity or through an incision to access a treatment site. The
inspection fiber can enable the operator to monitor the treatment
and manipulate the shockwave applicator accordingly.
In one embodiment of the invention the tip of the shockwave
applicator along with an optical fiber can be incorporated into a
flexible endoscope suitable for subcutaneous catheter delivery and
optical imaging can be employed to enable treated sites to be
visually monitored.
In some embodiments of the processes of the present invention, one
or more of a number of treatment parameters to facilitate or
improve performance of the treatment can be adjusted and improved
or optimized for a particular application, for example by
manipulation of an appropriate control, or instrument or other
device by the surgeon or other operator. These parameters include
the orientation, location and/or disposition of the shockwave
applicator, the application of saline or other irrigation fluid,
the application of suction, and any one or more of the energy
parameters employed to generate the applied pressure pulses. The
energy parameters include the intensity, frequency, and pulse
duration of the pressure pulses.
In the treatment of concealed treatment sites, adjustment of the
treatment parameters can be facilitated by providing illumination
means at the treatment site to illuminate the treatment site, as
described herein. This measure can permit the surgeon, or other
operator, to adjust one or more of the treatment parameters
according to what he or she sees at the treatment site.
Accordingly, some embodiments of the invention comprise
illuminating the treatment site.
One embodiment of shockwave applicator useful for practicing the
invention is illustrated in the drawings. Other embodiments will
be, or become, apparent to a person of ordinary skill in the art in
light of the disclosure herein.
Referring to FIG. 1 of the drawings, the distal tip 1 of the
shockwave applicator comprises a titanium or stainless steel target
2, an optical fiber 3 which terminates adjacent target 2 and a
passage 4 for irrigation fluid. Pulsed laser energy propagated
along optical fiber 3 strikes target 2 causing ionization of the
target material and inducing a plasma 5. Laser-induced plasma 5
causes a shockwave to be generated and to exit the shockwave
applicator through opening 6 in the direction of the arrow 7.
Irrigation fluid supplied in the direction of arrow 8 can clean and
remove debris from target 2 and the treatment site.
Titanium can be useful as a target material for the purposes of the
invention, for its good bio-compatibility and high absorption
coefficient with respect to the laser wavelength and for its
thermal conductivity. The latter properties can be useful in
avoiding propagation of laser energy or heat externally of the
shockwave applicator, which could adversely impact sensitive tissue
at the treatment site. Other embodiments of the invention can
employ stainless steel, zirconium or another suitable target
material.
In one embodiment of the shockwave applicator shown in FIG. 1
opening 6 has a diameter of about 0.8 mm, distal tip 1 has a width
of about 1.4 mm and the distance between the end of optical fiber 3
and target 2, the fiber-to-target distance, can be in the range of
from about 0.7 to about 1.5 mm, for example about 1 mm.
The shockwave applicator shown in FIGS. 2-5 of the drawings,
referenced 10, is suitable for application of laser-induced
shockwaves to the sinuses and other areas. Shockwave applicator 10
comprises a proximal barrel portion 12 and an elongated distal
needle portion 14.
Barrel portion 12 can be suitable for gripping and manipulating the
instrument in one hand and can, as shown, be cylindrical and/or be
provided with gripping structure, here shown as a plurality of
circumferential ribs 16, or can employ other gripping structures,
if desired. Barrel portion 12 can have a longitudinal axis (not
referenced) along which it has a generally straight, or rectilinear
configuration, as shown. Alternatively, barrel portion 12 can be
curved, or angled to facilitate its manipulation, or to serve other
purposes, if desired.
Proximally, barrel portion 12 has an optical connector 18 to
provide an optical fiber connection to a suitable laser source (not
shown). Shockwave applicator 10 comprises an optical fiber 20 which
extends through shockwave applicator 10 from connector 18 to a
point close to the distal tip of shockwave applicator 10, as will
be explained. Optical fiber 20 can be a component of shockwave
applicator 10 which makes an optical connection at optical
connector 18 with another optical fiber leading from the laser
source. Alternatively, optical fiber 20 can be a portion of the
optical fiber leading from the external laser source which optical
fiber portion can be threaded through shockwave applicator 10 via
optical connector 18.
A further connector, irrigation connector 22, located at the
proximal end of shockwave applicator 10 permits shockwave
applicator 10 to be connected to a supply of saline, or other
suitable irrigation fluid. An irrigation passageway 24 extends
through both barrel portion 12 and needle portion 14 of shockwave
applicator 10 to supply irrigation fluid distally to the work site,
if desired.
Needle portion 14 of shockwave applicator 10 can be formed
integrally with barrel portion 14 or can be permanently or
separably attachable thereto. In the embodiment of the invention
shown, needle portion 14 has three sections: an elongated proximal
section 26, a curved section 28 and a distal tip 30. The several
sections of needle portion 14 of shockwave applicator 10 can
comprise a integral structure or can comprise separate units
permanently or detachably assembled together, if desired. Needle
portion 14, or one or more sections thereof can be rigid, or if
desired can be flexible to facilitate delivery to the treatment
site.
Proximal section 26 is straight in the illustrated embodiment and
extends along the longitudinal axis of the barrel portion, but
could be curved or angled. Proximal section 26 serves to reach into
inaccessible sites, for example to extend through the sino-nasal
tract to reach a sinus. Curved section 28 serves to give distal tip
30 a desired orientation to address the treatment site. Proximal
section 26 and curved section 28, as illustrated, have
approximately constant cross-sectional shapes along their lengths
but could be tapered in the distal direction, if desired, or have
other variations in their cross-sectional shapes along their
lengths.
Distal tip 30 outputs the treatment phases to the treatment site.
In the illustrated embodiment, the configuration of curved section
28 can be such as to orient distal tip 30 at an angle to the
perpendicular to the longitudinal axis of shockwave applicator 10
suitable for treatment of a sinus region or other desired treatment
site. For example, distal tip 30 can be employed to address any one
of the maxillary, ethmoid, sphenoid and frontal sinuses. The angle
can be in the range of from about 40.degree. to about 60.degree.,
for example about 50.degree., or can have another desired
value.
As shown in FIG. 5, distal tip 30 comprises a short straight
section of shockwave applicator 10 having a generally triangular
cross-section. Distal tip 30 comprises a generally flat upper
surface 32 abutted by a lefthand target surface 34 and a righthand
surface 36 each of which extends along distal tip 30 and meets
upper surface 32 at an acute angle.
Target surface 34 of distal tip 30 can be flat or slightly convex
and comprises the surface on which the laser beam output from
optical fiber 20 impinges. The material of distal tip 30 at target
surface 34 desirably can be selected to facilitate generation of a
shockwave when impinged by the laser beam. For this purpose, all or
a part of distal tip 30, including target surface 34, can be formed
of a suitable ionizable material, for example a metal such as
stainless steel, titanium or zirconium. Desirably, distal tip 30
can be constructed so that little or no clinically significant heat
is generated externally of distal tip 30 in a way that could be
damaging to tissue at the treatment site. This can be done by
constituting distal tip 30 in the vicinity of target surface of
sufficient heat conductive material as to form a heat sink.
Furthermore, it can be desirable to avoid extraneous laser energy
escaping distal tip 30 and impinging on tissue by employing for
target surface 34 a material having a high absorption coefficient
with respect to the laser wavelength, for example, titanium,
stainless steel, zirconium or the like.
Optical fiber 20 terminates at any suitable location where it can
output a laser beam to strike or impinge lefthand surface 34 so as
to generate a shockwave. For example, optical fiber 20 can
terminate at the distal end of curved section 28 of needle portion
14 of shockwave applicator 10. This termination is not shown in the
drawings. The distally terminal end of optical fiber 20 desirably
can be oriented to direct the laser beam on to lefthand surface 34
to generate a shockwave. For example, the optical fiber can
terminate at a modest acute angle to the axis of distal tip 30 and
direct the output laser beam toward the end of lefthand surface
34.
Righthand surface 36 can be somewhat concave and can provide an
alternative target surface, if desired, which is employable with
minor reconfiguration of the terminal end of optical fiber 20 to
direct the laser beam on to righthand surface 36 rather than on to
lefthand target surface 34. If desired, righthand surface 36 can be
employed as an alternative laser beam target surface providing,
with its different topography a modified shockwave pattern compared
with that generated by lefthand surface 34. In another embodiment
of the invention, lefthand and righthand surfaces 34 and 36 have
similar topographies and the one can be utilized when the other
becomes worn.
Desirably, during shockwave generation, irrigation fluid can be
delivered to flow coaxially to the fiber distal surface plane to
preventing debris accumulating at the light-emitting fiber surface,
which could cause damage to or breakage of the fiber. The
irrigation fluid can also flow across the laser target surface, if
desired, and can exit shockwave applicator 10 along either or both
of surfaces 34 and 36 as appropriate. For this purpose, irrigation
passageway 24 can have one or two irrigation fluid outlets (not
shown) at the distal end of curved section 28 of needle portion 14
of shockwave applicator 10, or in another suitable location, if
desired. Also, irrigation fluid supplied through shockwave
applicator 10 can be used to irrigate the treatment site, if
desired.
In one embodiment of the treatment method of the invention, when
the laser is activated, pulses of laser light are output from
optical fiber 24 and impinge on the ionizable material of the
lefthand surface 34 of distal tip 30 causing heating, ionization
and the generation of a shock wave which may have a pattern such as
illustrated schematically by reference numeral 38. In the
embodiment shown, shockwave pattern 38 can generate forwardly of
shockwave applicator 10 with an expanding front in a direction
angled downwardly from the axis along distal tip 30. The
configuration of shockwave applicator 10 can impede propagation of
shockwaves in the opposite direction, helping to concentrate the
energy in the direction of the expanding front.
Such a pattern is believed useful for treatment of sinus and other
relatively small areas and facilitates concentration of the energy
in the shockwave pulses on the targeted biofilm. Desirably, the
shockwave pattern can be concentrated within a limited geometric
volume in front of shockwave applicator 10 so as to project the
energy forwardly so that it can be directed toward the target
treatment site rather than dispersing in all directions. Other
shockwave patterns 38 can be employed as will be apparent to those
skilled in the art.
The embodiment of shockwave applicator 10 shown in FIG. 6 is
generally similar to that shown in FIGS. 2-5 with the difference
that a modified curved section 128 is employed which has a greater
curvature so that distal tip 30 extends along a line at an angle
closer to the perpendicular to the longitudinal axis of barrel
portion 12 of shockwave applicator 10. This angle can be in the
range of from about 10.degree. to about 25.degree., for example
about 18.degree., or can have another desired value.
Shockwave applicator 10 can be disposable, being used for one or
possibly more treatments of a single patient. Alternatively,
shockwave applicator 10 can be reusable and sterilizable. Shockwave
applicator 10 can have any suitable dimensions. Some embodiments of
shockwave applicator 10 have an overall length, as viewed in FIG.
3, of from about 150 mm to about 250 mm, for example about 200 mm,
barrel portion 12 and needle portion 14 being in proportion.
Barrel portion 12 can have any suitable transverse dimensions that
are comfortable and efficient for the user, for example a
physician. The transverse dimensions of needle portion 14 can be
adapted to the intended target anatomy. For sinus applications, the
largest transverse dimensions of those parts of needle portion 14
that are intended to enter the sino-nasal tract to access one or
more sinuses desirably is relatively small for example not more
than about 5 mm. In some embodiments, the largest transverse
dimension of distal tip 30, of curved section 28 and optionally
also of proximal section 26 of needle portion 14 is not more than
about 3 mm. This dimension can be 2 mm or less, for example in the
range of from about 1 mm to about 1.5 mm.
The thinness of needle portion 14 can be helpful when inserting
shockwave applicator 10 into a bodily cavity of a patient to reach
inaccessible sites such as a sinus site. In these embodiments of
the invention, optical fiber 20 is desirably sufficiently thin to
be accommodated within a thin needle portion 14, having a diameter,
for example, in the range of from about 0.1 mm to about 1 mm (from
about 100 .mu.m to about 1,000 .mu.m). Some embodiments of optical
fiber 20 can have a diameter in the range of from about 0.2 mm to
about 0.5 mm (from about 200 .mu.m to about 500 .mu.m).
Usefully, to treat inaccessible sinus, otological or other sites,
needle portion 14 can include a distal length of at least about 20
mm, for example from about 30 mm to about 50 mm, which has a
cross-section sufficiently small to be received into the nose and
the sino-nasal tract.
Any suitable laser system can be employed to provide laser energy
to optical fiber 3 of the shockwave applicator illustrated in FIG.
1. One example of a suitable laser system comprises a Nd:YAG laser
operating in the infrared at a wavelength of 1064 nm, which can be
Q-switched to provide high intensity energy pulses, if desired.
Using an optical fiber 3 of diameter 283 .mu.m, the Nd:YAG laser
system can be employed to generate pulsed laser energy with a pulse
length of about 4 ns (nanoseconds), a frequency of from about 1 to
about 10 Hz and with an energy of from about 10 to about 15 mJ. If
desired, the laser system can include a control computer and a
video display to monitor performance.
One treatment process utilizing the illustrated shockwave
applicator comprises inspecting a treatment site harboring a
biofilm or otherwise diagnosing a condition appropriate for
treatment by a laser-induced shockwave process according to the
invention and determining a suitable treatment protocol. For
example, distal tip 30 of the illustrated shockwave applicator is
then inserted into the bodily cavity constituted by the patient's
nostril, through the naris, and is manipulated to address the
internal bodily site to be treated, for example a sinus.
When shockwave applicator 10 is properly positioned, the laser
source is activated to supply a desired dosage of laser pulses
along optical fiber 20. In one embodiment of the invention the
treatment site is positioned in front of laser target surface 34
with respect to the laser or optical fiber 20. The laser energy
strikes target surface 34 of distal tip 30, generating shockwave 38
which is applied to the treatment site. Shockwave 38 is generated
in the fluid medium, air, irrigation fluid or the like, on the same
side of the target surface as is impinged by the laser beam and in
some cases will have a direction of propagation which is
approximately in the direction of reflection of the laser beam from
the target surface, or in the direction the laser beam would have
been reflected if not absorbed by the target.
Desirably, during treatment, the distance from the closest point of
distal tip 1 to the treatment site is in the range of from about
0.5 mm to about 10 mm, for example from about 1 mm to about 5 mm,
and so far as is practical, the distance is maintained, for example
by suitable manipulation of the shockwave applicator by the
user.
It is contemplated that the effect of the laser-induced shockwaves
impacting on biofilm present at the target site, including biofilm
adhered to tissue at the treatment site, will be to attenuate,
disrupt, disperse or weaken the biofilm or to cause the biofilm to
lose its integrity or lose adherence to its substrate or to cause
one or more pieces to break away. Multiple ones of these results
may occur and the biofilm may be destroyed partially or entirely.
Dosages can be increased and treatments can be repeated to increase
biofilm attrition, if desired. Dosages can be controlled to limit
collateral tissue damage or inflammation which it is believed can
be controlled to be little or modest, or not visibly apparent,
employing dosages such as are described herein.
Subsequently to, or concurrently with, application of laser-induced
shockwaves, irrigation fluid can be supplied via irrigation
connector and irrigation passageway 24 to remove debris including
biofilm detritus, if generated, and clean distal tip 30 and the
treatment site.
If desired, an endoscope (not shown) can be employed with the
illustrated shockwave applicator to view the treatment process and
treatment site and the endoscope may comprise a video camera or
other suitable optics. The endoscope can be used simultaneously
with the use of the illustrated shockwave applicator to apply
shockwaves or it can be employed to inspect the treatment site
before and after treatment. Also, if desired, the illustrated
shockwave applicator can be modified for endoscopic delivery to the
treatment site.
If desired, the laser-induced shockwave treatments of the invention
can be accompanied by or followed by local or systemic
administration of an antibiotic to limit or control possible
infection associated with dispersal of the targeted biofilm.
Some examples of antibiotics that can be employed include one or
more compounds selected from the group consisting of cefmetazole,
cefazolin, cephalexin, cefoxitin, cephacetrile, cephaloglycin,
cephaloridine, cephalosporin c, cephalotin, cephamycin a,
cephamycin b, cephamycin c, cepharin, cephradine, ampicillin,
amoxicillin, hetacillin, carfecillin, carindacillin, carbenicillin,
amylpenicillin, azidocillin, benzylpenicillin, clometocillin,
cloxacillin, cyclacillin, methicillin, nafcillin,
2-pentenylpenicillin, penicillin n, penicillin o, penicillin s,
penicillin v, chlorobutin penicillin, dicloxacillin, diphenicillin,
heptylpenicillin, and metampicillin. Other suitable antibiotics
will be or become apparent to a person of ordinary skill in the
art.
Treatment systems according to the invention can include a
shockwave applicator such as the illustrated shockwave applicator
and a laser system selected and tuned to supply appropriate laser
energy to the illustrated shockwave applicator. The treatment
apparatus can also include associated computing and display
equipment and, optionally, an endoscope for treatment site
inspection, process monitoring and/or instrument delivery.
As stated, the second step of a biofilm treatment process according
to the invention can comprise applying an antimicrobial dosage of
light and the biofilm treatment systems can comprise an appropriate
light applicator.
The term "light" is used herein to include visible wavelength
radiation, as well as near-visible infrared radiation or
ultraviolet radiation, useful for the purposes of the invention, in
the range of from about 200 nm up to about 1500 nm in wavelength.
Monochromatic or polychromatic light sources can be employed. Other
radiant energies, such as heat or RF energy, can be included with
the applied light energy radiation, provided they do not cause
adverse side effects, for example undue heating of tissue. In one
embodiment of the invention, at least 50 percent of the applied
radiant energy is visible or near infrared light.
Usefully, antimicrobial treatments employed in the practice of the
invention can comprise a microorganism-reducing light dosage having
an energy and duration sufficient to reduce the microorganism
population yet which is insufficient to cause tissue damage or pain
to the treated subject.
Suitable light energy can be provided for an antimicrobial
treatment by employing a laser, laser diode, light-emitting diode
or other light source capable of outputting light at a wavelength
or wavelengths in a range of from about 200 nm to about 1500 nm. If
desired the light energy may be output in a range of from about 400
nm to about 1200 nm. In one embodiment of the invention, at least
80 percent of the energy is output in a visible wavelength range of
from about 400 nm to about 700 nm.
In some embodiments of the invention, the light energy does not
include, and can substantially exclude ultraviolet wavelengths. For
example in these embodiments, no more than about 10 percent,
desirably no more than about 5 percent, or 1 percent, of the light
energy is at wavelengths below about 380 nm.
If desired, the methods of the invention can include the applying
of a colorant to the treatment site and optionally to one or more
other sites whence biofilm components may be dispersed, to
photosensitive the target microorganism to complementary visible
wavelengths in the dosage of light to be applied. Colorant
application can comprise crushing a colorant applicator containing
a frangible capsule of colorant fluid and applying colorant to the
target structures with the colorant applicator or in another
suitable manner.
In embodiments where a colorant is employed, the method can use a
laser source to generate the attenuating radiation which supports
output of light radiation at a wavelength in a range of from about
400 nm to about 700 nm, the colorant and radiation wavelength being
selected for absorption of the radiation by the colorant. For
example the colorant can be methylene blue or toluidine blue and
relatively red or orange, complementary light of wavelength of
about 630-660 nm may be employed. Using rose Bengal, complementary
wavelengths of about 400-500 nm can be employed.
In some embodiments of the invention, no colorant is employed.
Useful antimicrobial treatments for these embodiments can employ a
laser source capable of generating infrared light at a wavelength
in a range of from about 850 nm to about 950 nm.
The microorganism-reducing light can be applied at any suitable
energy level and duration, which parameters can be determined by
routine experimentation. One example is at an energy level of from
about 1 mW to about 200 mW for a duration sufficient to deliver
from about 0.2 to about 20 Joules.
In another example, the microorganism-reducing radiation is applied
at from about 10 mW to about 100 mW for a duration sufficient to
deliver from about 2 to about 10 Joules.
Antimicrobial light treatment of subjects can be effected by a
medical professional or other suitable individual, employing a
light applicator with any suitable light energy-generating system
or light source. For example, a laser having a maximum power input
of about 3 watts and supporting light output of from about 900 to
about 940 nm can be employed. The laser can be used with a SMA
connector and an optical fiber having a diameter of about 400 to
about 800 micron, for example about 600 micron. The optical fiber
can have any suitable tip for example a tip having an external
diameter of about 1.5 mm, and a diffuser of length of about 10-20
mm. A fiber length of 0.5 to 1.5 meters can be convenient. Some
other specifications can comprise an optical fiber of from about
100 to about 1200 micron diameter, a tip having an external
diameter of from about 0.5 to about 2 mm, and a diffuser of length
of from about 3 to about 30 mm.
A useful antimicrobial treatment duration can be in the range of
from about 30 seconds to about 15 minutes. The invention includes
embodiments wherein the antimicrobial treatment duration is from
about 1 minute to about 10 minutes, for example from about 2 to
about 5 minutes.
The method of the invention can comprise providing a subject with a
personal light applicator to enable the subject to self-administer
an antimicrobial treatment in place of or as an adjunct to
professionally applied antimicrobial treatment. An example of one
useful device for this purpose is a BioNase (trademark)
phototherapy system supplied by Syro Technologies R & D Ltd.,
of Jaffa, Israel. This product is a pocket-sized unit with dual
output outputting red light at 6 mW per nostril timed for a
treatment duration of about 4.5 minutes. Such a device can include
a nasal clip, clampable to the septum, to support the device for
self-administration.
One example of the antimicrobial treatment method comprises
applying a liquid colorant to a treatment site, for example the
nasal cavity of the subject, and possibly also one or more sinus
cavities, inserting a light transmissive nasal dilator through a
naris of the subject to dilate the nostril of the subject,
inserting a light output member into the nasal dilator and
activating a light source to deliver light through the nasal
dilator to the anterior nasal cavity of the subject. The light
output member can comprise a fiber optic tip communicating with a
remote light source, a support-mounted light-emitting diode, or
other suitable light source.
In one example of the practice of the invention, the antimicrobial
treatment is carried out to effect a microorganism count reduction
of at least about 50 percent. In another embodiment, the
antimicrobial treatment is carried out to effect a microorganism
count reduction of at least about 80 percent. The antimicrobial
treatment can be carried out to effect a microorganism count
reduction of at least about 90 percent or of at least about 95
percent. The invention includes embodiments wherein the
microorganism count reduction effected is higher than 95 percent,
for example in the range of from 98 to 100 percent. A desired
reduction can be effected in a single antimicrobial treatment, or
as a result of multiple antimicrobial treatments having cumulative
effect.
The antimicrobial treatment can be repeated with any desired
frequency, for example, within about 1 to 7 days, or otherwise as
will be apparent to a person of ordinary skill in the art.
Referring to FIGS. 7 and 8, the light applicator here shown,
reference 58, is suitable for partial insertion into a nasal or
other bodily cavity and comprises a generally cylindrical hand
piece 60 on which a light tube 62 is supported as a distal
extension thereof. Nasal light applicator 58 further comprises a
sheathed optical fiber 64 which extends longitudinally through hand
piece 60 and into light tube 62 and a light source (not shown), for
example a laser, a laser diode, a light-emitting diode, a gas
discharge lamp, a flash lamp, an intense pulsed light or another
suitable light source, to supply light to optical fiber 64 in a
controllable manner.
Hand piece 60 can be embodied as a disposable unit, if desired
which can be dedicated to a single patient or other treatment
subject. Some embodiments of hand piece 60 are releasably
attachable to optical fiber 64, so that, if desired, each patient
can be treated with a new or dedicated unit embodying essentially
all the surfaces likely to be contacted by the patient or the
physician, technician or other user. If desired, hand piece 60 can
be provided in a variety of sizes for patients with different
anatomies. The dimensions and other structural characteristics of
nasal light applicator 58 can also be varied to provide units of
different functionality, for example a tip-of-the-nose probe, a
deep nasal probe or other desired nasal light applicator.
Individual hand pieces 60 can be sterilized and sealed in their own
wrapper, if desired.
Optical fiber 64 has a portion within light tube 62 from which the
sheathing has been removed to provide a length of exposed fiber 66
from which light transmitted along optical fiber 64 can radiate
laterally, and in other directions, to be applied to the treatment
site.
Light tube 62 comprises a transparent or translucent outer cover 67
and a cylindrical diffuser 68 disposed within outer cover 67 and
around exposed fiber 66. Cylindrical diffuser 68 can have a
transparent or translucent appearance and can be formed of frosted
or whitened or other suitable diffusing material. In one embodiment
of the invention, cylindrical diffuser 68 completely surrounds
exposed fiber 66 to diffuse light emitted from exposed fiber 66 and
scatter it laterally of light tube 62. If desired, outer cover 67
can be disposable. One or more outer covers 67 can be packaged with
hand piece 60, if desired, or they can be packaged separately.
Both outer cover 67 and cylindrical diffuser 68 desirably have good
light transmissivity for the treatment light and can be formed of
any suitably transmissive material, such as acrylic or
polycarbonate plastic, or glass. Optionally, cylindrical diffuser
68 can have a light transmissivity which is limited to a selected
waveband and can, if desired, be a light filter, for example an
orange or red filter.
Cylindrical diffuser 68 can be supported in any suitable manner.
For example, cylindrical diffuser 68 can have a base portion 70
supported by hand piece 60. Optionally, cylindrical diffuser 68 can
have a tip portion 72 which tapers distally and supports the distal
tip 74 of optical fiber 64 and can, if desired have a small
aperture or recess to receive and locate distal tip 74 of optical
fiber 64. If desired, for example for structural stability, tip
portion 72 of optical fiber 64 can be sheathed. Also, base portion
70, or other relevant hand piece structure, can be reflective to
block light traveling proximally and redirect it distally.
In one embodiment of the invention, a shield or mask (not shown) is
provided around, or partially replacing, cylindrical diffuser 68 to
limit the output light pattern to a desired window, for example, a
selected radial angle.
In some embodiments of the invention, light tube 62 is dimensioned
to be receivable into a patient's nostril and can be provided in
different sizes according to an intended patient's anatomy. To this
end, hand piece 60 can include a number of outer covers 67 for
light tube 62 which have different diameters and lengths. Some
exemplary lengths of outer cover 67, measured to shoulder 76 of
hand piece 60, can be in a range of from about 5 mm to about 30 mm,
desirably from about 10 mm to about 20 mm. Some exemplary diameters
of outer cover 67, can be in a range of from about 3 mm to about 20
mm, desirably from about 5 mm to about 10 mm.
Usefully, outer cover 67 can be configured and dimensioned to
function as a nasal dilator, for example by selecting its
dimensions, in relation to a particular patient so that the
patient's nostril will be appropriately dilated, as described
herein, when light tube 62 is inserted into the patient's nostril.
In one embodiment of the invention, the patient's nostril is
significantly distended when light tube 62 is sufficiently inserted
to illuminate the interior of the nostril, including the nasal
vestibule.
Externally, the embodiment of hand piece 60 shown has an ergonomic
structure enabling it to be easily and conveniently manipulated,
for example in the manner of a pen or pencil, by gripping it
between the thumb and forefingers. Other suitable shapes or
configurations of hand piece 60 will be apparent to a person of
ordinary skill in the art. Some optional external structural
features of hand piece 60 include a smooth beveled shoulder 76,
recesses 78 and elongated, slender overall proportions.
Shoulder 76 of hand piece 60 can abut the patient's nostril and
prevent over-insertion of light tube 62 into the nostril, in some
cases. Optionally, and depending upon the particular patient,
shoulder 76 and light tube 62 may adequately dilate the patient's
nostril without use of a separate instrument such as nasal dilator
12. Recesses 78 can comprise small depressions suited to be engaged
by the tips of a user's thumb and/or fingers, to facilitate control
and manipulation of hand piece 60.
Internally, hand piece 60 has a hollow longitudinal cavity 80 to
accommodate optical fiber 64 to which hand piece 60 can be secured
by suitable clamping or other means. In some useful embodiments of
the invention, hand piece 60 is releasably attachable to optical
fiber 64. This capability can permit the tension in the fiber to be
adjusted and allow for replacement of worn or damaged fiber either
by moving hand piece 60 along optical fiber 64 to a new length of
fiber, or by complete replacement of the fiber. In another
embodiment of the invention, hand piece 60 is permanently attached
to optical fiber 64.
Various mechanical arrangements for releasably attaching hand piece
60 to optical fiber 64 will be or become apparent to a person of
ordinary skill in the art. For example, handpiece 60 can be formed
in two sections, namely a body section 82 and an end section 84
which are screwed together by means of threads 86, the sections
meeting joining at a band 88. Screwing the sections together brings
thread 86 on body section 82 into engagement with a ball clamp 87.
Ball clamp 87 is resiliently compressible and has an axial opening
(not shown) to receive optical fiber 64. As body section 82 and end
section 84 are tightened together, the thread 86 on body section 82
bears down on ball clamp 87 compressing it around, and locking it
on to, optical fiber 64 desirably without shifting optical fiber 64
axially.
Optionally, end section 84 of hand piece 60 can have a short end
sleeve 90 through which optical fiber 64 can be inserted into hand
piece 60. Desirably, end sleeve 90 can frictionally grip optical
fiber 64 to act as a strain relief device preventing external
strains being transmitted to ball clamp 82 and other downstream
structures.
To further stabilize the mounting of hand piece 60 on optical fiber
64, a number, for example three or four, of circumferentially
arranged and radially extending contoured guide ribs 92 can be
provided in body section 82 of hand piece 60 towards its distal
end. Guide ribs 92 can center optical fiber 64, and optionally can
slidingly engage it with limited pressure, helping to position
optical fiber 64 in light tube 62.
Outer cover 67 of light tube 62 can be attached to hand piece 60 in
any suitable manner, desirably in a removable manner. For example,
outer cover 67 can be a snap fit into a recess in the forward or
distal end of body section 82 of hand piece 60, and can, if desired
be locked in place by rotational engagement of detent such as
detents 94, providing a quickly connected fitting that is easily
manipulated by a busy physician or other operator.
Body section 82 and end section 84 of hand piece 60 can be
manufactured in any suitable manner from appropriate materials, for
example by molding from plastics materials. For example, the more
complex body section 82 can be fabricated from polycarbonate or the
like, and the simpler end section 84 can also be fabricated from
polycarbonate or from a polyolefin, or an acrylic polymer or
copolymer or the like.
In one method of use of nasal light applicator 58 a physician, an
infection control nurse clinician, or other appropriate technician,
or operator, unwraps a new or sterilized hand piece 60 and selects
a light tube outer cover 67 of appropriate size for the patient to
be treated. If necessary, an existing outer cover 67 can be removed
from the hand piece 60 and one of appropriate size can be quickly
snapped into place. Alternatively, the outer cover 67 of
appropriate size can be fitted to hand piece 60 after the latter is
assembled to optical fiber 64, which assembly is described
below.
The hand piece 60 is assembled with optical fiber 64 by first
unscrewing end section 82 from body section 84 of hand piece 60 to
sufficiently to open ball clamp 87. Optical fiber 84, with a
section of sheathing removed to provide a suitable length of
exposed fiber 66 at its distal end, is then manually threaded
through end sleeve 90, through ball clamp 87 and between guide ribs
92 to emerge into light tube 62 where its distal tip can be
advanced to engage with tip portion 72 of cylindrical diffuser 68.
End section 84 is then screwed into body section 82 to lock ball
clamp 87 onto optical fiber 64 and provide a secure, integral
assembly. Disassembly of hand piece 60 from optical fiber 84 can be
quickly accomplished by reversing the assembly procedure. Employing
some embodiments of the invention, both assembly and disassembly
can readily be accomplished without the use of tools.
The proximal end of optical fiber 64 is then connected to a light
source, if not already connected, and nasal light applicator 58 is
ready for use.
To apply a light treatment to the patient's nostril, the physician
or other user, the physician can grip hand piece 60 in one hand and
gently insert light tube 62 through the naris into the patient's
nostril with sufficient penetration to provide a desired field of
illumination within the nostril. The depth of penetration can for
example be about 8 mm to 12 mm in pediatric cases or from about 15
mm to about 20 mm in adult cases.
After insertion of light tube 62, the physician switches the light
source causing light to radiate from exposed fiber 66 and diffuse
through cylindrical diffuser 68 to illuminate the interior of the
patient's nostril with light of the selected wavelength or
waveband. For example, nostril can be illuminated coaxially and
homogeneously with the illumination in the direction of the
mechanical axis of the fiber being prevented. If desired, colorant
can be applied inside the nostril before applying the light
treatment.
In some useful embodiments of the invention the ergonomic design of
hand piece 60 enables it to be conveniently gripped, permitting the
physician or other holder to effect a carefully controlled
insertion of light tube 62 into the patient's nostril, with fine
movements to position hand piece 60, as desired for one or more
light treatments, for example for treatments at different depths of
penetration or different angles. Hand piece 60 is held in place in
the patient's nostril for the duration of each treatment, for
example for from about 1 to about 3 minutes.
When one nostril has been adequately treated hand piece 60 is moved
to the other nostril and a similar treatment is performed. If
desired, outer cover 67 can be removed and a new outer cover 67 can
be fitted to hand piece 60 for treating the patient's other nostril
to avoid cross-contaminating the nostrils. Optionally, the two
outer covers 67 can be identified with respect to the nostril for
which they have been used and used for the same nostril in future
treatments of the particular patient. Thus, it is possible to
dedicate a hand piece 60 to a particular patient and to dedicate
one or more outer covers 67 to each of the patient's individual
nostrils. Both hand piece 60 and the outer covers 67 can be re-used
in future treatments of the patient and disposed of at the end of a
course of treatment, or when no longer serviceable. A new, or newly
sterilized, hand piece 60 is employed for the next patient.
By employing a slightly oversized outer cover 67, stretch the
internal skin of the nostril can be stretched as light tube 62 is
introduced into the nostril, exposing the hair within the nostril
and baring the inner lining the skin of the nostril, to facilitate
illumination of the inner lining of the nasal skin for desired
period of time. A tight fit of light tube 62 within the nostril can
help keep the tip of the applicator instrument in a fixed
position.
In summary, nasal light applicator 58, as illustrated in FIGS. 7-8,
can be embodied as a disposable unit to be used for a single
patient to control contamination from patients carrying pathogenic
bacteria. Since the distal end of the hand piece 60 is inserted
into the patient's nostril, a disposable cover is provided which
can be replaced easily between nostrils and potentially used in
multiple applications in the same patient.
While nasal light applicator 58 has been described with reference
to the example of the application of treatments by a medical
professional, it will be understood that the invention includes
embodiments of nasal light applicator 58 that are suitable for home
use or for self administration.
Some non-limiting examples of the practice of the processes of the
invention in vitro will now be described which illustrate methods
and materials that can be employed in practicing the claimed
invention. In vitro results that can be obtained will also be
described.
EXAMPLE 1
Destruction of a Biofilm
A sample biofilm is treated with laser-generated shockwaves
employing a pulsed Nd:YAG laser at a wavelength of 1064 nm. The
laser output energy is between about 8 mJ and about 12 mJ. The
laser is pulsed using passive Q-switch pulsing with a pulse length
between about 4 ns and about 8 ns. The laser energy is delivered to
the biofilms using a shockwave applicator intended for cataract
surgery such as is described in Dodick U.S. Pat. No. 5,906,611. As
described in the Dodick patent, in the shockwave applicator, an
optical fiber tip outputting laser pulses is aimed at a titanium
target producing plasma and generating a shockwave.
Distally, the shockwave applicator employed comprises a disposable
needle or probe instrument in the form of a hollow metal 1.2 mm
diameter tube coupled with an optical fiber of diameter about 300
.mu.m at one end and with a 0.7 mm opening at the other end. The
laser beam propagates axially inside the tube and hits a titanium
target, positioned adjacent and above the opening at the tip of the
probe to output shockwaves through the opening. The shockwave
applicator has a passageway for irrigation fluid which outputs
adjacent the shockwave opening.
To apply shockwaves to the biofilm, the shockwave applicator can be
moved toward the samples and then maintained at a distance of about
5 mm to 10 mm from the biofilm while operating the laser to
generate shockwaves. The shockwaves can be initiated by a series of
low energy laser pulses in a slow stream of irrigation liquid. A
488 nm laser is used to excite the yellow fluorescent protein and
488 nm and 543 nm laser lines are used to excite the propidium
iodide treated samples.
During treatment of the biofilm with the Nd:YAG laser a time-lapse
imaging function is used to capture images in the transmitted mode.
Image rendering is effected by confocal stacks and time series are
rendered using Imaris BITPLANE (trademark) image rendering
software.
During exposure to the shockwaves generated by the Nd:YAG laser
each biofilm can be seen to oscillate in response to laser pulses
directed at the biofilm from a distance in excess of about 10 mm.
As the shockwave applicator approaches the target area to a
distance of about 5 mm to about 10 mm away, while generating
laser-induced shockwaves, in most cases, some of the biofilm is
disrupted and detached immediately. Generally, the rest of the
biofilm detaches after exposure to a number of pulses, i.e. about
10 to about 20 shockwaves. Following the clearing of the biofilm
from its host surface, the attached and previously protected
bacteria can be seen floating in the liquid medium. The applied
shockwave treatment clearly disrupts the biofilms and exposes the
protected microorganisms. The exposed biofilm bacteria are
accordingly rendered more susceptible to antibiotics or other
anti-infective therapeutic modalities.
No visible damage to the biofilm support structure resulting from
the shockwave treatments may be apparent.
EXAMPLE 2
Two Step Treatment of Biofilm
A number of biofilms of S. aureus Xen 31, a stable bioluminescent
clinical methicillin-resistant Staphylococcus aureus, construct,
are grown in a 96 well microtiter plate for 48 hours. The study
includes the following seven trials: a) control; b) ciprofloxacin
alone (at 3 mg/L, an established minimum inhibitory concentration);
c) shockwave treatment alone; d) near infrared laser alone e)
shockwave treatment and ciprofloxacin; f) shockwave treatment plus
near infrared laser treatment; and g) shockwave treatment, near
infrared laser and ciprofloxacin.
The shockwave treatment is carried out with a Q-switched Nd-YAG
laser set with a frequency of 1 pulse per second at a wavelength of
1,064 nm and output energy for the laser system of from about 8 to
about 12 mJ. Each biofilm treated is exposed to 10-20 pulses of
shockwave placed in each of the tested wells. The near infrared
treatment is carried out with a 940 nm diode constant output near
infrared laser applied for a duration of 180 seconds with an energy
level of 3 W with a distance between the well and the probe set
constantly to cover the entire well diameter of 0.7 cm diameter
providing a power density of about 7.8 W/cm.sup.2. Given the
duration of 180 seconds, the total energy density is about 1400
joule/cm.sup.2.
The results are evaluated with a biophotonic system from IVIS
Technologies for determining live bacteria concentrations, and by
determining optical density ("OD"), to determine total bacteria
concentrations.
Some results which can be obtained are shown below where the
percentages given are percentage reductions in bacterial colony
count in the samples, as determined, respectively, by optical
density measurement or by the IVIS instrument.
TABLE-US-00001 IVIS Trial OD Instrument a) control b) ciprofloxacin
alone 44% 58% c) shockwave treatment alone 15% 8% d) near infrared
laser alone 20% an increase e) shockwave plus ciprofloxacin 79% 81%
(P < 0.05) f) shockwave plus near infrared 43% 88% (P < 0.05)
g) shockwave plus near infrared 81% 85% (P < 0.05) plus
ciprofloxacin
The confidence level is shown parenthetically for the more
significant results.
These results suggest that the antibiotic ciprofloxacin alone
provides a partial reduction in bacterial density. Trials with
shockwaves or infrared light alone provided little or no reduction.
With a combination of the shockwave treatment and near infrared
treatment, but no antibiotic, there is a 43% reduction in OD
(P<0.05), which is much greater than either energy treatment
alone, suggesting that the biofilm may be disrupted. Also, the
combined two step energy treatment exhibits a surprising 88%
reduction (P<0.05) in the live bacteria count. In contrast,
ciprofloxacin alone resulted in a decrease of only 28% of total
live cells, comprising biofilm remaining attached and disrupted
planktonic cells, and 58% of biofilm cells (both P>0.05).
Ciprofloxacin in combination with shockwave treatment and shockwave
treatment plus the near infrared laser shows a decrease of over 60%
in total live biomass and over 80% of biofilm cells, which is
significantly greater than ciprofloxacin alone (P<0.05).
Biofilms are becoming regarded as an integral part of chronic
rhinosinusitis pathology. Bacteria in biofilm communities may
display significantly greater resistance to traditional
antimicrobial therapies than their planktonic (mobile)
counterparts. Shockwave treatments such as are described in Example
1 can successfully disrupt a biofilm in vitro, and can apparently
remove the biofilm in first step. Example 2 illustrates two step
processes which can include killing the biofilm.
While the invention is not limited by any particular theory, the
two step bacteria killing process can be explained by hypothesizing
that the first step converts the bacteria from the biofilm forming
state to a dispersed and detached floating state wherein a second
strike can be inflicted. The second strike can comprise a
relatively weak diffuse, infrared laser, or an antibiotic or both
infrared light and an antibiotic.
A possible explanation for the slight significance of the
ciprofloxacin containing trial versus the laser only trial is a
temperature rise to over 44 C..degree. rendering the antibiotic
less active. Such a temperature rise may be a possible explanation
for the bactericidal effect of the laser.
A person of ordinary skill in the art will understand that in vivo
results may be different from the in vitro results described
herein.
The ability to clean and remove biofilm from complex, delicate
implant materials, without damage, which can be provided by
embodiments of the inventive processes and systems has useful
application in a variety of fields including, for example, for
cleaning biofilm-contaminated cardiac implants and associated
devices and materials.
As has been referenced herein, the invention includes embodiments
wherein the described laser-induced shockwave technology is coupled
with endoscopic techniques to facilitate the visualization of, and
access to, in vivo biofilms, facilitating the treatment of deeper
tissue infections.
Another embodiment of the invention comprises a process for
treating biofilms comprising employment of a laser-induced
shockwave generating instrument for cellular level ablation or
"shaving" of a biofilm resident in vivo. For example, the process
can comprise selectively removing a first layer of biofilm with an
initial shockwave application, followed by one or more additional
shockwave applications to remove additional layers of the biofilm.
Each shockwave application can comprise traversing the shockwave
across the biofilm by suitably manipulating the instrument. The
biofilm can comprise invasive pathogens and the initial shockwave
application can expose the invasive pathogens or other
microorganisms for destruction by additional shockwaves, or in
other desired manner. Subsequent shockwave applications can
similarly expose layers of microorganisms deeper in the biofilm. If
desired, any suitable antimicrobial therapy can be employed for
treating the bacteria or other microorganisms exposed and dispersed
after disruption of the biofilm.
A further embodiment of shockwave applicator according to the
invention comprises illumination means or an illumination device to
illuminate the target area to facilitate monitoring of the
treatment. If desired, the illumination means can comprise an
illumination fiber having a proximal light input end communicating
with a light source and having a distal light output end locatable
in the vicinity of the treatment site to illuminate the treatment
site. The illumination fiber can be movable with the shockwave
applicator. For example it may be a component of the shockwave
applicator or it can be a separate device. Illumination means not
only can be usefully employed to illuminate concealed treatment
sites but may also be useful for treatment of biofilms resident at
exposed treatment sites.
Other shockwave or pressure pulse generators that can be employed
in the practice of the present invention include piezoelectric, for
example piezoceramic, devices, spark discharge devices,
electromagnetically or inductively driven membrane pressure
shockwave generators or pressure pulse generators and generators
that employ pressure currents or jets associated with the transport
of material. The pressure pulse generator can be disposed in the
shockwave applicator or externally in a separate unit connected to
the shockwave applicator by a transmission line, if desired.
Such other pressure pulse generators may provide useful shockwaves
or pressure pulses for biofilm disruption or attenuation, without
use of laser or other photic energy, as will be understood by those
skilled in the art.
The energy output of some of the herein described embodiments of
shockwave applicator are flexibly controllable and accurate and
well suited to treatment of mammalian host resident biofilms. For
example, a number of the parameters of such shockwave applicators
can be manipulated and varied, including for example, the laser
energy and pulse frequency, the optical fiber thickness, the
fiber-to-target distance and the geometry of the distal output
opening through which the shockwave generates to impinge on a
target organ, or other output structure, to vary the output. Any
one or more of these and other parameters is, or are, available for
adjustment to adapt the applied energy, the energy concentration at
the treatment site, the energy duration, the pattern of application
and other factors, for any particular treatment. Thus, the
invention can provide a user with a flexible treatment process and
instrument which can be adapted, without difficulty, to treat
biofilms in a variety of locations in a mammalian body.
The processes and systems of the invention employing
laser-generated or other shockwave or pressure wave technology can
be useful for disruption or other treatment of host-resident
biofilms in otolaryngology and other fields. Some embodiments of
the invention are contemplated as having safety parameters when
employed for biofilm treatment that allow treatments to be effected
in close proximity to sensitive and critical anatomical structures,
including for example, cranial nerves and large blood vessels.
Furthermore, the mechanical nature of the laser generated shockwave
that is applied to the biofilm, in some embodiments of the
invention avoids the issues of toxicity and acquired resistance
commonly associated with high and/or repeated doses of
antibiotics.
The foregoing detailed description is to be read in light of and in
combination with the preceding background and invention summary
descriptions wherein partial or complete information regarding the
best mode of practicing the invention, or regarding modifications,
alternatives or useful embodiments of the invention may also be set
forth or suggested, as will be apparent to one skilled in the art.
The description of the invention is intended to be understood as
including combinations of the various elements of the invention,
and of their disclosed or suggested alternatives, including
alternatives disclosed, implied or suggested in any one or more of
the various methods, products, compositions, systems, apparatus,
instruments, aspects, embodiments, examples described in the
specification or drawings, if any, and to include any other written
or illustrated combination or grouping of elements of the invention
or of the possible practice of the invention, except for groups or
combinations of elements that will be or become apparent to a
person of ordinary skill in the art as being incompatible with or
contrary to the purposes of the invention.
Throughout the description, where processes are described as
having, including, or comprising specific process steps, it is
contemplated that compositions of the present invention can also
consist essentially of, or consist of, the recited components, and
that the processes of the present invention can also consist
essentially of, or consist of, the recited processing steps. It
should be understood that the order of steps or order for
performing certain actions is immaterial so long as the invention
remains operable. Moreover, two or more steps or actions may be
conducted simultaneously.
While illustrative embodiments of the invention have been described
above, it is, of course, understood that many and various
modifications will be apparent to those of ordinary skill in the
relevant art, or may become apparent as the art develops, in the
light of the foregoing description. Such modifications are
contemplated as being within the spirit and scope of the invention
or inventions disclosed in this specification.
* * * * *